Breast Cancer Treatment–for health professionals (PDQ®)

General Information About Breast Cancer

This summary discusses primary epithelial breast cancers in women. The breast is rarely affected by other
tumors such as lymphomas, sarcomas, or melanomas. Refer to the following PDQ summaries for more information on these cancer types:

Incidence and Mortality

Estimated new cases and deaths from breast cancer (women only) in the United States in 2015:[1]

New cases: 231,840.

Deaths: 40,290.

Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 60,290 cases of in situ disease, 231,840 new cases of invasive disease, and 40,290 deaths expected in 2015.[1] Thus, fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 71,660 American women will die of lung cancer in 2015.[1] Men account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section in the PDQ summary on Breast Cancer Screening for more information).

Widespread adoption of screening increases breast cancer incidence in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). (Refer to the Ductal Carcinoma In Situ section in the Breast Cancer Diagnosis and Pathology section in the PDQ summary on Breast Cancer Screening for more information.) Population studies from the United States [2] and the United Kingdom [3] demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.[4]

Age-specific risk estimates are available to help counsel and design
screening strategies for women with a family history of breast cancer.[43,44]

Of all women with breast cancer, 5% to 10% may have a germline
mutation of the genes BRCA1 and BRCA2.[45] Specific mutations of BRCA1 and
BRCA2 are more common in women of Jewish ancestry.[46] The estimated lifetime
risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is
40% to 85%. Carriers with a history of breast cancer have an increased risk of
contralateral disease that may be as high as 5% per year.[47] Male BRCA2 mutation carriers also have an increased risk of breast cancer.[48]

(Refer to the PDQ summary on Breast Cancer Prevention for more information about factors that decrease the risk of breast cancer.)

Screening

Clinical trials have established that screening asymptomatic women using mammography, with or
without clinical breast examination, decreases breast cancer mortality.
(Refer to the PDQ summary on Breast Cancer Screening for more information.)

Diagnosis

Patient evaluation

When breast cancer is suspected, patient management generally
includes the following:

Confirmation of the diagnosis.

Evaluation of the stage of disease.

Selection of therapy.

The following tests and procedures are used to diagnose breast cancer:

Mammography.

Ultrasound.

Breast magnetic resonance imaging (MRI), if clinically indicated.

Biopsy.

Contralateral disease

Pathologically, breast cancer can be a multicentric and bilateral disease.
Bilateral disease is somewhat more common in patients with infiltrating lobular
carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk.[71-73] The development of a contralateral breast cancer is associated with
an increased risk of distant recurrence.[74] When BRCA1/BRCA2 mutation carriers were diagnosed before age 40 years, the risk of a contralateral breast cancer reached nearly 50% in the ensuing 25 years.[75,76]

Patients who have breast cancer will undergo bilateral
mammography at the time of diagnosis to rule out synchronous disease. To
detect either recurrence in the ipsilateral breast in patients treated
with breast-conserving surgery or a second primary cancer in the contralateral
breast, patients
will continue to have regular breast physical examinations and mammograms.

The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is occurring more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.[77-79]

Prognostic Factors

Breast cancer is commonly treated by various combinations of surgery, radiation
therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy
may be influenced by the following clinical and pathology features (based on conventional histology and immunohistochemistry):[80]

The menopausal status of the patient.

The stage of the
disease.

The grade of the primary tumor.

The estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.

The histologic type. Breast
cancer is classified into a variety of histologic types, some of which have
prognostic importance. For example, favorable histologic types include
mucinous, medullary, and tubular carcinomas.[81-83]

The use of molecular profiling in breast cancer includes the following:[84]

Although certain rare inherited mutations,
such as those of BRCA1 and BRCA2, predispose women to develop breast cancer, prognostic
data on BRCA1/BRCA2 mutation carriers who have developed breast cancer are conflicting; these women are at greater risk of developing contralateral breast cancer.

Posttherapy Considerations

Hormone replacement therapy

After careful consideration, patients with severe symptoms may be treated with hormone replacement therapy. For more information, refer to the following PDQ summaries:

Histopathologic Classification of Breast Cancer

Table 1 describes the histologic classification of breast cancer based on tumor location.[1]
Infiltrating or invasive ductal cancer is the most common breast cancer
histologic type and comprises 70% to 80% of all cases.

Stage Information for Breast Cancer

The American Joint Committee on Cancer (AJCC) staging system provides a
strategy for grouping patients with respect to prognosis. Therapeutic
decisions are formulated in part according to staging categories but primarily
according to the following:

Tumor size.

Lymph node status.

Estrogen-receptor and progesterone-receptor
levels in the tumor tissue.

Human epidermal growth factor receptor 2 (HER2/neu) status.

Menopausal status.

General health of the
patient.

Definitions of TNM and AJCC Stage Groupings

The AJCC has designated staging by tumor, node, and metastasis (TNM) classification to define breast cancer.[1] When this system was modified in 2002, some nodal categories that were previously considered stage II were reclassified as stage III.[2] As a result of the stage migration phenomenon, survival by stage for case series classified by the new system will appear superior to those using the old system.[3]

bThe T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria, or both. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 1.1 mm is reported as 1 mm, or a size of 2.01 cm is reported as 2.0 cm. Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over clinical determination of T size.

cInvasion of the dermis alone does not qualify as T4.

TX

Primary tumor cannot be assessed.

T0

No evidence of primary tumor.

Tis

Carcinoma in situ.

Tis (DCIS)

DCIS.

Tis (LCIS)

LCIS.*

Tis (Paget)

Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.

T1

Tumor ≤20 mm in greatest dimension.

T1mi

Tumor ≤1 mm in greatest dimension.

T1a

Tumor >1 mm but ≤5 mm in greatest dimension.

T1b

Tumor >5 mm but ≤10 mm in greatest dimension.

T1c

Tumor >10 mm but ≤20 mm in greatest dimension.

T2

Tumor >20 mm but ≤50 mm in greatest dimension.

T3

Tumor >50 mm in greatest dimension.

T4

Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules).c

T4a

Extension to the chest wall, not including only pectoralis muscle adherence/invasion.

T4b

Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which do not meet the criteria for inflammatory carcinoma.

bClinically detected is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be designated in site-specific factors as clinical, fine-needle aspiration, core biopsy, or sentinel lymph node biopsy. Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment.

bClassification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (SN) for "sentinel node," for example, pN0(SN).

c"Not clinically detected" is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical examination.

d"Clinically detected" is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine-needle aspiration biopsy with cytologic examination.

Note: ITCs are defined as small clusters of cells ≤0.2 mm, or single tumor cells, or a cluster of <200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by IHC methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.

Metastases in clinically detectedd ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes.

OR

Metastases in >3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected.c

pN3c

Metastases in ipsilateral supraclavicular lymph nodes.

Posttreatment ypN

–Posttreatment yp "N" should be evaluated as for clinical (pretreatment) "N" methods above. The modifier "SN" is used only if a sentinel node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by AND.

–The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed.

No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow, or other nonregional nodal tissue that are ≤0.2 mm in a patient without symptoms or signs of metastases.

cT0 and T1 tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.

–M0 includes M0(i+).

–The designation pM0 is not valid; any M0 should be clinical.

–If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of response to neoadjuvant therapy.

–Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received neoadjuvant therapy.

–Postneoadjuvant therapy is designated with "yc" or "yp" prefix. No stage group is assigned if there is a complete pathologic response (CR) to neoadjuvant therapy, for example, ypT0ypN0cM0.

Ductal Carcinoma In Situ

Introduction

Ductal carcinoma in situ (DCIS) is a noninvasive condition. DCIS can progress to become invasive cancer, but estimates of the likelihood of this vary widely. Some people include DCIS in breast cancer statistics. The frequency of the diagnosis of DCIS has increased markedly in the United States since the widespread use of screening mammography. In 1998, DCIS accounted for about 18% of all newly diagnosed invasive plus noninvasive breast tumors in the United States.

Very few cases of DCIS present as a palpable mass;
80% are diagnosed by mammography alone.[1] DCIS comprises a heterogeneous
group of histopathologic lesions that have been classified into several
subtypes based primarily on architectural pattern: micropapillary, papillary,
solid, cribriform, and comedo. Comedo-type DCIS consists of cells that appear
cytologically malignant, with the presence of high-grade nuclei,
pleomorphism, and abundant central luminal necrosis. Comedo-type DCIS appears
to be more aggressive, with a higher probability of associated invasive ductal
carcinoma.[2]

Treatment Option Overview

Until recently, the customary treatment of DCIS was mastectomy.[1] The
rationale for mastectomy included a 30% incidence of multicentric disease, a
40% prevalence of residual tumor at mastectomy following wide excision alone,
and a 25% to 50% incidence of breast recurrence following limited surgery for
palpable tumor, with 50% of those recurrences being invasive carcinoma.[1,3]
The combined local and distant recurrence rate following mastectomy is 1% to
2%.
No randomized comparisons of mastectomy versus breast-conserving surgery plus breast radiation are available.

In view of the success of breast-conserving surgery combined with breast radiation for invasive carcinoma, this conservative approach was extended to the noninvasive entity. To determine whether breast-conserving surgery plus radiation therapy was a reasonable approach to the management of DCIS, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the European Organisation for Research and Treatment of Cancer (EORTC) have each completed prospective randomized trials in which women with localized DCIS and negative surgical margins following excisional biopsy were randomized to either breast radiation (50 Gy) or to no further therapy.[4-7]

Of the 818 women enrolled in the NSABP-B-17 trial, 80% were diagnosed by mammography, and 70% of the patients' lesions were 1 cm or less. At the 12-year actuarial follow-up interval, the overall rate of in-breast tumor recurrence was reduced from 31.7% to 15.7% when radiation therapy was delivered (P < .005). Radiation therapy reduced the occurrence of invasive cancer from 16.8% to 7.7% (P = .001) and recurrent DCIS from 14.6% to 8.0% (P = .001).[7][Level of evidence: 1iiDii] Nine pathologic features were evaluated for their ability to predict for in-breast recurrence, but only comedo necrosis was determined to be a significant predictor for recurrence.

Similarly, of the 1,010 patients enrolled in the EORTC-10853 trial, mammography detected lesions in 71% of the women. At a median follow-up of 10.5 years, the overall rate of in-breast tumor recurrence was reduced from 26% to 15% (P < .001) with a similarly effective reduction of invasive (13% to 8%, P = .065) and noninvasive (14% to 7%, P = .001) recurrence rates.[7][Level of evidence: 1iiDii] In this analysis, parameters associated with an increased risk of in-breast recurrence included age 40 years or younger, palpable disease, intermediate or poorly differentiated DCIS, cribriform or solid growth pattern, and indeterminate margins. Elsewhere, margins of less than 1 mm have been associated with an unacceptable local recurrence rate, even with radiation therapy.[8] In both of the studies reported here, the effect of radiation therapy was consistent across all assessed risk factors.

Given that lumpectomy and radiation therapy are generally applicable for most
patients with DCIS, can a subset of patients be identified with such a low risk
of local recurrence that postoperative radiation therapy can be omitted? To identify such a favorable group of patients, several pathologic
staging systems have been developed and tested retrospectively, but consensus
recommendations have not been achieved.[10-13]

The Van Nuys Prognostic Index, which combines three predictors of local recurrence (i.e., tumor size, margin
width, and pathologic classification), was used to retrospectively analyze 333
patients treated with either excision alone or excision and radiation
therapy.[13] Using this prognostic index, patients with favorable lesions, who
received surgical excision alone, had a low recurrence rate (i.e., 2% with a median
follow-up of 79 months). A subsequent analysis of these data was performed to
determine the influence of margin width on local control.[14] Patients whose
excised lesions had margin widths 10 mm or larger in every direction
had an extremely low probability of local recurrence with surgery alone (4%
with a mean follow-up of 8 years). These reviews
are retrospective, noncontrolled, and are subject to substantial selection
bias. By contrast, no subset of patients was identified in the
prospective NSABP trial that did not benefit from the addition of radiation
therapy to lumpectomy in the management of DCIS.[2,4,9,15]

To determine if tamoxifen adds to the efficacy of local
therapy in the management of DCIS, the NSABP performed a double-blind
prospective trial (NSABP-B-24) of 1,804 women.[16] Patients were randomly assigned to
lumpectomy, radiation therapy (50 Gy), and placebo versus lumpectomy, radiation
therapy, and tamoxifen (20 mg/day for 5 years).[16] Positive or unknown
surgical margins were present in 23% of patients. Approximately 80% of the
lesions measured not larger than 1 cm, and more than 80% were detected
mammographically. Breast cancer events were defined as the presence of new
ipsilateral disease, contralateral disease, or metastases. Women in the
tamoxifen group had fewer breast cancer events at 5 years than did those on a
placebo (8.2% vs. 13.4%; P = .009).[16][Level of evidence: 1iDii] With
tamoxifen, ipsilateral invasive breast cancer decreased from 4.2% to 2.1% at 5
years (P = .03). Tamoxifen also decreased the incidence of contralateral breast
neoplasms (invasive and noninvasive) from 0.8% per year to 0.4% per year
(P = .01). The benefit of tamoxifen extended to those patients with positive or
uncertain margins.[17] (Refer to the PDQ summary on Breast Cancer Prevention
for more information.)

Treatment Options for Patients With DCIS

Breast-conserving surgery and radiation therapy with or without tamoxifen.

Total mastectomy with or without tamoxifen.

Breast-conserving surgery without radiation therapy. A large national
clinical trial by the Radiation Therapy Oncology Group (RTOG-9804) comparing breast-conserving surgery and tamoxifen with or
without radiation therapy was closed due to poor accrual, and results are pending.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
ductal breast carcinoma in situ. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction and sentinel node biopsy with or without axillary lymph node dissection for positive SLNs.

Postoperative radiation therapy:

Axillary node–negative breast cancer (postmastectomy):

No additional therapy.

Radiation therapy.

Axillary node–positive breast cancer (postmastectomy):

For one to three nodes, the role of regional radiation therapy to the infra/supraclavicular nodes, internal mammary nodes, axillary nodes, and chest wall is unclear.

For four or more nodes or extranodal involvement, regional radiation therapy is advised.

Surgery

Stage I, II, IIIA, and operable IIIC breast cancer often require a multimodal approach to
treatment. The diagnostic
biopsy and surgical procedure that will be used as primary treatment should be
performed as two separate procedures:

Biopsy. In many cases, the diagnosis of breast
carcinoma is made by core needle biopsy.

Surgical procedure. After the presence of a malignancy is
confirmed by biopsy, the following surgical treatment options can be discussed
with the patient before a therapeutic procedure is selected:

Breast-conserving surgery.

Modified radical mastectomy (removal of the entire breast with axillary dissection of levels I and II) with or without breast reconstruction.

To guide the selection of adjuvant therapy, many factors including stage, grade, and molecular status of the tumor (e.g., ER, PR, HER2/neu, or triple-negative status) are considered.[1-5]

Local-regional treatment

Selection of a local therapeutic approach depends on the
following:[6]

Location and size of the lesion.

Analysis of the mammogram.

Breast size.

Patient’s desire to preserve the breast.

Options for surgical management of the primary tumor include the following:

Breast-conserving
surgery plus radiation therapy. All histologic types of invasive breast cancer may be treated with
breast-conserving surgery plus radiation therapy.[7] However, the presence of inflammatory breast cancer, regardless of histologic subtype, is a contraindication to breast-conserving therapy. The presence of
multifocal disease in the breast and a history of collagen vascular disease are
relative contraindications to breast-conserving therapy.

Mastectomy with or without breast reconstruction.

Surgical staging of the axilla should also be performed.

Survival is
equivalent with any of these options, as documented in the European Organization for Research and Treatment of Cancer's trial (EORTC-10801) [8] and other prospective randomized trials.[9-15] Also, a retrospective study of 753 patients who were divided into three groups based on hormone receptor status (ER-positive or PR-positive; ER-negative and PR-negative but HER2/neu-positive; and triple-negative) found no differences in disease control within the breast in patients treated with standard breast-conserving surgery; however, there are not yet substantive data to support this finding.[16]

The rate of local
recurrence in the breast with conservative treatment is low and varies slightly
with the surgical technique used (e.g., lumpectomy, quadrantectomy, segmental
mastectomy, and others). Whether completely clear
microscopic margins are necessary has been debated.[17-19]
However, a multidisciplinary consensus panel recently used margin width and ipsilateral breast tumor recurrence from a meta-analysis of 33 studies (N = 28,162 patients) as the primary evidence base for a new consensus regarding margins in stage I and stage II breast cancer patients treated with breast-conserving surgery plus radiation therapy. Results of the meta-analysis include the following:[20]

Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) were associated with a twofold increase in the risk of ipsilateral breast tumor recurrence compared with negative margins.

More widely clear margins were not found to significantly decrease the rate of ipsilateral breast tumor recurrence compared with no ink on tumor. Thus, it was recommended that the use of no ink on tumor be the new standard for an adequate margin in invasive cancer.

There was no evidence that more widely clear margins reduced ipsilateral breast tumor recurrence for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.

Axillary lymph node management

Axillary node status remains the most important predictor of outcome in breast cancer patients. Evidence is insufficient to recommend that lymph node staging can be omitted in most patients with invasive breast cancer. Several groups have attempted to define a population of women in whom the probability of nodal metastasis is low enough to preclude axillary node biopsy. In these single-institution case series, the prevalence of positive nodes in patients with T1a tumors ranged from 9% to 16%.[21,22] Another series reported the incidence of axillary node relapse in patients with T1a tumors treated without axillary lymph node dissection (ALND) was 2%.[23][Level of evidence: 3iiiA]

The axillary lymph nodes are staged to aid in determining prognosis and
therapy. SLN biopsy is the initial standard axillary staging procedure performed in women with invasive breast cancer. The SLN is defined as any node that receives drainage directly from the primary tumor; therefore, allowing for more than one SLN, which is often the case. Studies have shown that the injection of technetium-labeled sulfur colloid, vital blue dye, or both around the tumor or biopsy cavity, or in the subareolar area, and subsequent drainage of these compounds to the axilla results in the identification of the SLN in 92% to 98% of patients.[24,25] These reports demonstrate a 97.5% to 100% concordance between SLN biopsy and complete ALND.[26-29]

On the basis of the following body of evidence, SLN biopsy is the standard initial surgical staging procedure of the axilla for women with invasive breast cancer. SLN biopsy alone is associated with less morbidity than axillary lymphadenectomy.

Evidence (SLN biopsy):

A randomized trial of 1,031 women compared SLN biopsy followed by ALND when the SLN was positive with ALND in all patients.[30][Level of evidence 1iiC]

Quality of life at 1 year (as assessed by the frequency of patients experiencing a clinically significant deterioration in the Trial Outcome Index of the Functional Assessment of Cancer Therapy-Breast scale) was superior in the SLN biopsy group (23% vs. 35% deteriorating in the SLN biopsy vs. ALND groups, respectively; P = .001). Arm function was also better in the SLN group.

The National Surgical Adjuvant Breast and Bowel Project’s (NSABP-B-32 [NCT00003830]) multicenter phase III trial randomly assigned women (N = 5,611) to either SLN plus ALND or SLN resection alone, with ALND only if the SLNs were positive.[31][Level of evidence: 1iiA]

On the basis of the following trial results, ALND is unnecessary after a positive SLN biopsy in patients with limited SLN-positive breast cancer treated with breast conservation or mastectomy, radiation, and systemic therapy.

A multicenter, randomized clinical trial sought to determine whether ALND is required after an SLN biopsy reveals an SLN metastasis of breast cancer. This phase III noninferiority trial planned to randomly assign 1,900 women with clinical T1 or T2 invasive breast cancer without palpable adenopathy and with one to two SLNs containing metastases identified by frozen section to undergo ALND or no further axillary treatment. All patients underwent lumpectomy, tangential whole-breast radiation therapy, and appropriate systemic therapy; OS was the primary endpoint. Because of enrollment challenges, a total of 891 women out of a target enrollment of 1,900 women were randomly assigned to one of the two treatment arms.[32][Level of evidence: 1iiA]

ALND and axillary radiation therapy provided excellent and comparable axillary control for patients with T1 or T2 primary breast cancer and no palpable lymphadenopathy who underwent breast-conserving therapy or mastectomy.

The use of axillary radiation therapy was also associated with significantly less morbidity.

For patients who require an ALND, the standard evaluation usually involves only a level I and II dissection, thereby removing a satisfactory number of nodes for evaluation (i.e., at least 6–10), while reducing morbidity from the procedure.

Breast reconstruction

For patients who opt for a total mastectomy, reconstructive surgery may be
performed at the time of the mastectomy (i.e., immediate reconstruction)
or at some subsequent time (i.e., delayed reconstruction).[35-38] Breast contour can
be restored by the following:

Submuscular insertion of an artificial implant
(silicone- or saline-filled). If an immediate implant cannot technically be performed,
a tissue expander can be inserted beneath the pectoral muscle. Saline is
injected into the expander to stretch the tissues for a period of weeks or
months until the desired volume is obtained. The tissue expander is then
replaced by a permanent implant. (Visit the U. S. Food and Drug Administration's [FDA's website] for more
information on breast implants.)

Rectus muscle or other flap. Muscle flaps require a
considerably more complicated and prolonged operative procedure, and blood
transfusions may be required.

After breast reconstruction, radiation
therapy can be delivered to the chest wall and regional nodes in either the
adjuvant or local recurrent disease setting. Radiation therapy after
reconstruction with a breast prosthesis may affect cosmesis, and the incidence
of capsular fibrosis, pain, or the need for implant removal may be
increased.[39]

Postoperative Radiation Therapy

Radiation therapy is regularly employed after breast-conserving surgery. Radiation therapy is also indicated for high-risk postmastectomy patients. The main goal of adjuvant radiation therapy is to eradicate residual disease thus reducing local recurrence.[40]

Post–breast-conserving surgery

For women who are treated with breast-conserving surgery without radiation therapy, the risk of recurrence in the conserved breast is substantial (>20%) even in confirmed axillary lymph node–negative women.[41] Although all trials assessing the role of radiation therapy in breast-conserving therapy have shown highly statistically significant reductions in local recurrence rate, no single trial has demonstrated a statistically significant reduction in mortality. However, a large meta-analysis demonstrated a significant reduction in risk of recurrence and breast cancer death.[42] Thus, evidence supports the use of whole-breast radiation therapy after breast-conserving surgery.

Evidence (breast-conserving surgery followed by radiation therapy):

A 2011 meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), which included over 10,000 women with early-stage breast cancer, supported whole-breast radiation therapy after breast-conserving surgery.[42][Level of evidence: 1iiA]

With regard to radiation dosing and schedule, the following has been noted:

Whole-breast radiation dose. Conventional whole-breast radiation therapy is delivered to the whole breast (with or without regional lymph nodes) in 1.8 Gy to 2 Gy daily fractions over about 5 to 6 weeks to a total dose of 45 Gy to 50 Gy.

Radiation boost. A further radiation boost is commonly given to the tumor bed. Two randomized trials conducted in Europe have shown that using boosts of 10 Gy to 16 Gy reduces the risk of local recurrence from 4.6% to 3.6% at 3 years (P = .044),[43][Level of evidence: 1iiDiii] and from 7.3% to 4.3% at 5 years (P < .001).[44][Level of evidence: 1iiDiii] Results were similar after a median follow-up of 17.2 years.[45][Level of evidence: 1iiDii] If a boost is used, it can be delivered either by external-beam radiation therapy, generally with electrons, or by using an interstitial radioactive implant.[46]

Radiation schedule. Some studies show that a shorter fractionation schedule of 42.5 Gy over 3 to 4 weeks is a reasonable alternative for some breast cancer patients.

Postmastectomy

Postoperative chest wall and regional lymph node adjuvant radiation therapy has traditionally been given
to selected patients considered at high risk for local-regional failure
after mastectomy.
Patients at highest risk for local recurrence have one or more of the following:[49-51]

Four or more
positive axillary nodes.

Grossly evident extracapsular nodal extension.

Large
primary tumors.

Very close or positive deep margins of resection of the
primary tumor.

In this high-risk group, radiation therapy can decrease local-regional recurrence, even among those patients who receive adjuvant chemotherapy.[52]

Patients with one to three involved nodes without any of the high-risk factors are at low risk of local recurrence, and the value of routine use of adjuvant radiation therapy in this setting is unclear.

Evidence (postoperative radiation therapy in patients with one to three involved lymph nodes):

The 2005 EBCTCG meta-analysis of 42,000 women in 78 randomized treatment comparisons indicated that radiation therapy is beneficial, regardless of the number of lymph nodes involved.[40][Level of evidence: 1iiA]

In subgroup analyses, the 5-year local recurrence rate was reduced by 12% (95% CI, 8%–16%) for women with one to three involved lymph nodes and by 14% (95% CI, 10%–18%) for women with four or more involved lymph nodes. In an updated meta-analysis of 1,314 women with axillary dissection and one to three positive nodes, radiation therapy reduced locoregional recurrence (2P < .00001), overall recurrence (RR, 0.68; 95% CI, 0.57–0.82; 2P = .00006), and breast cancer mortality (RR, 0.80; 95% CI, 0.67–0.95; 2P = .01).[53][Level of evidence: 1iiA]

In contrast, for women at low-risk of local recurrence with node-negative disease, the absolute reduction in 5-year local recurrence was only 4% (P = .002; 95% CI, 1.8%–6.2%), and there was not a statistically significant reduction in 15-year breast cancer mortality (absolute gain, 1.0%; P > .1; 95% CI, -0.8%–2.8%).

Further, an analysis of NSABP trials showed that even in patients with large (>5 cm) primary tumors and negative axillary lymph nodes, the risk of isolated local-regional recurrence was low enough (7.1%) that routine local-regional radiation therapy was not warranted.[54]

Timing of postoperative radiation therapy

The optimal sequence of adjuvant chemotherapy and radiation therapy after
breast-conserving surgery has been studied. Based on the following studies, delaying radiation therapy for several months after
breast-conserving surgery until the completion of adjuvant chemotherapy does not appear to have a negative impact on overall outcome. Additionally, initiating chemotherapy soon after breast-conserving surgery may be preferable for patients at high risk of distant dissemination.

Chemotherapy first (n = 122), consisting of cyclophosphamide, methotrexate, fluorouracil (5-FU), and prednisone (CMFP) plus doxorubicin
repeated every 21 days for four cycles, followed by breast radiation.

Breast
radiation first (n = 122), followed by the same chemotherapy.

The following results were observed:

With a median
follow-up of 5 years, OS was 73% for the radiation-first group
and 81% for the chemotherapy-first group (P = .11).

The 5-year crude rate of first recurrence by site was 5% in the radiation-first group and
14% in the chemotherapy-first group for local recurrence
and 32% in the radiation-first group and 20% in the chemotherapy-first group for distant or regional recurrence or both. This difference in
the pattern of recurrence was of borderline statistical significance (P = .07).

Further analyses revealed that differences in recurrence patterns persisted for
most subgroups with the exception of those who had either negative tumor
margins or one to three positive lymph nodes. For these two subgroups, sequence
assignment made little difference in local or distant recurrence rates,
although the statistical power of these subgroup analyses was low.

Potential
explanations for the increase in distant recurrence noted in the radiation-first group are that chemotherapy was delayed for a median of 17 weeks
after surgery, and that this group received lower chemotherapy dosages because of
increased myelosuppression.

Two additional randomized trials, though not specifically designed to address
the timing of radiation therapy and adjuvant chemotherapy, do add useful
information.

In the NSABP-B-15 trial, patients who had undergone
breast-conserving surgery received either one course of CMF (n = 194) followed by
radiation therapy followed by five additional cycles of CMF, or they received four
cycles of doxorubicin and cyclophosphamide (AC) (n = 199) followed by radiation therapy.[56][Level of evidence: 1iiA]

No differences in
DFS, distant DFS, and OS were
observed between these two arms.

The International
Breast Cancer Study Group trials VI and VII also varied the timing of
radiation therapy with CMF adjuvant chemotherapy and reported results similar to NSABP-B-15.[57]

These studies showed
that delaying radiation therapy for 2 to 7 months after surgery had no effect
on the rate of local recurrence.
These findings have been confirmed in a meta-analysis.[58][Level of evidence: 1iiA]

In an unplanned analysis of patients treated on a phase III trial evaluating the benefit of adding trastuzumab in HER2/neu-positive breast cancer patients, there was no associated increase in acute adverse events or frequency of cardiac events in patients who received concurrent adjuvant radiation therapy and trastuzumab.[59] Therefore, delivering radiation therapy concomitantly with trastuzumab appears to be safe and avoids additional delay in radiation therapy treatment initiation.

Late toxic effects
of radiation

Late toxic effects of radiation therapy are uncommon, and can be minimized with current
radiation delivery techniques and with careful delineation of the target
volume. Late effects of radiation include
the following:

Radiation pneumonitis. In a retrospective analysis of 1,624 women treated with conservative surgery and
adjuvant breast radiation at a single institution, the overall incidence of
symptomatic radiation pneumonitis was 1.0% at a median follow-up of 77 months.[60]
The incidence of pneumonitis increased to 3.0% with the use of a supraclavicular
radiation field and to 8.8% when concurrent chemotherapy was administered.
The incidence was only 1.3% in patients who received sequential
chemotherapy.[60][Level of evidence: 3iii]

Cardiac events. Controversy existed as to whether adjuvant radiation therapy to the left chest wall or breast, with or without inclusion of the regional lymphatics, was associated with increased cardiac mortality. In women treated with radiation therapy before 1980, an increased cardiac death rate was noted after 10 to 15 years, compared with women with nonradiated or right-side-only radiated breast cancer.[52,61-63] This was probably caused by the radiation received by the left myocardium.

An analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program data from 1973 to 1989 reviewing deaths caused by ischemic heart disease in women who received breast or chest wall radiation showed that since 1980, no increased death rate resulting from ischemic heart disease in women who received left chest wall or breast radiation was found.[66,67][Level of evidence: 3iB]

Arm lymphedema. Lymphedema remains a major quality-of-life
concern for breast cancer patients. Single-modality treatment of the axilla
(surgery or radiation) is associated with a low incidence of arm edema.
In patients who receive axillary dissection, adjuvant radiation therapy increases the risk of arm edema. Edema occurs in 2% to 10% of patients who receive axillary dissection alone compared with 13% to 18% of patients who receive axillary dissection and adjuvant radiation therapy.[68-70] (Refer to the PDQ summary on Lymphedema for more information.)

Brachial plexopathy. Radiation injury to the brachial plexus after adjuvant nodal radiation therapy is
a rare clinical entity for breast cancer patients. In a single-institution
study using current radiation techniques, 449 breast cancer patients treated
with postoperative radiation therapy to the breast and regional lymphatics were
monitored for 5.5 years to assess the rate of brachial plexus injury.[71] The
diagnosis of such injury was made clinically with computerized tomography (CT) to
distinguish radiation injury from tumor recurrence. When 54 Gy in 30 fractions
was delivered to the regional nodes, the incidence of symptomatic brachial
plexus injury was 1.0%, compared with 5.9% when increased fraction sizes (45 Gy
in 15 fractions) were used.

Contralateral breast cancer. One report suggested an increase in contralateral breast
cancer for women younger than 45 years who received chest wall
radiation therapy after mastectomy.[72] No increased risk of contralateral
breast cancer occurred in women aged 45 years and older who received radiation
therapy.[73] Techniques to minimize the radiation dose to the contralateral
breast are used to keep the absolute risk as low as possible.[74]

Risk of second malignancy. The rate of second malignancy after adjuvant radiation therapy is very
low. Sarcomas in the treated field are rare, with a long-term risk of 0.2%
at 10 years.[75] In
nonsmokers, the risk of lung cancer as a result of radiation exposure during
treatment is minimal when current dosimetry techniques are used. Smokers,
however, may have a small increased risk of lung cancer in the ipsilateral
lung.[76]

Postoperative Systemic Therapy

Stage and molecular features determine the need for adjuvant systemic therapy and the choice of modalities used. For example, hormone receptor (ER and/or PR)–positive patients will receive hormone therapy. HER2 overexpression is an indication for using adjuvant trastuzumab, usually in combination with chemotherapy. When neither HER2 overexpression nor hormone receptors are present (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapeutic regimens, which may be combined with investigational targeted approaches.

An international consensus panel proposed a risk classification system and systemic therapy treatment options.[77] This classification, with
some modification, is described below:

May consider omitting chemotherapy plus anti-HER2, for small node-negative tumors

Triple-negative

Chemotherapy

May consider omitting CT, for small node-negative tumors

The selection of
therapy is most appropriately based upon knowledge of an individual’s
risk of tumor recurrence balanced against the short-term and long-term risks of
adjuvant treatment. This approach allows clinicians to help individuals
determine if the gains anticipated from treatment are reasonable for
their particular situation. The treatment options described below should be
modified based upon both patient and tumor characteristics.

Chemotherapy

The EBCTCG meta-analysis analyzed 11 trials that began from 1976 to 1989 in
which women were randomly assigned to receive regimens containing anthracyclines (e.g., doxorubicin or epirubicin) or CMF (cyclophosphamide, methotrexate and fluorouracil). The result of the overview analysis comparing CMF and
anthracycline-containing regimens suggested a slight advantage for the
anthracycline regimens in both premenopausal and postmenopausal women.[78]

Compared with CMF, anthracycline-based regimens were associated with a modest but statistically significant 11% proportional reduction in the annual risk of disease recurrence, and a 16% reduction in the annual risk of death. In each case, the absolute difference in outcomes between anthracycline-based and CMF-type chemotherapy was about 3% at 5 years and 4% at 10 years.[79][Level of evidence: 1iiA]

Of note, few women older than 70 years were studied, and specific conclusions could not be reached for this age group.

Importantly, these data were derived from clinical trials in which patients were not selected for adjuvant therapy according to hormone-receptor status, and the trials were initiated before the advent of taxane-containing, dose-dense, or trastuzumab-based therapy.[78] As a result, the data may not reflect treatment outcomes based on evolving treatment patterns.

Data from retrospective analyses of
randomized clinical trials suggest that, in patients with node-positive breast
cancer, the benefit from standard-dose versus lower-dose adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF),[2] or the
addition of doxorubicin to the adjuvant regimen,[3] is restricted to those
patients whose tumors overexpress HER2/neu.[Level of evidence: 1iiA]

A retrospective analysis of the HER2/neu status of 710 premenopausal, node-positive women was undertaken to see the effects of adjuvant chemotherapy with CMF or cyclophosphamide, epirubicin, and fluorouracil (CEF).[80][Level of evidence: 2A] HER2/neu was measured using fluorescence in situ hybridization, polymerase chain reaction, and immunohistochemical methods.

The study confirmed previous data indicating that the amplification of HER2/neu was associated with a decrease in relapse-free survival (RFS) and OS.

In patients with HER2/neu amplification, the RFS and OS were increased by CEF.

Similar results were seen in a meta-analysis that included 5,354 patients in whom HER2 status was known from eight randomized trials (including the one just described) comparing anthracycline-containing regimens with nonanthracycline-containing regimens.[81]

Adjuvant chemotherapy 2000s to present: The role of adding taxanes to adjuvant therapy

A number of trials have addressed the benefit of adding a taxane (paclitaxel or docetaxel) to an anthracycline-based adjuvant chemotherapy regimen for women with node-positive breast cancer.

Five-year absolute survival differences were 5% for DFS and 3% for OS in favor of taxane-containing regimens.

There were no differences in benefit observed in patient subsets defined by nodal status, hormone-receptor status, or age/menopausal status. There was also no apparent difference in efficacy between the two agents. However, none of the studies that were reviewed involved a direct comparison between paclitaxel and docetaxel.

A U.S. intergroup study (CLB-9344) randomly assigned women with node-positive tumors to three
dose levels of doxorubicin (60, 75, and 90 mg/m2) and a fixed
dose of cyclophosphamide (600 mg/m2) every 3 weeks for four cycles.
After AC (doxorubicin and cyclophosphamide) chemotherapy, patients were randomly assigned for a second time to paclitaxel
(175 mg/m2) every 3 weeks for four cycles or no further therapy, and women with
hormone receptor–positive tumors also received tamoxifen for 5 years.[83][Level of evidence: 1iiA]

Although the
dose-escalation of doxorubicin was not beneficial, the addition of paclitaxel
resulted in statistically significant improvements in DFS (5%) and
OS (3%).

The NSABP-B-28 trial randomly assigned 3,060 women with node-positive breast cancer to four
cycles of postoperative AC or four cycles of AC followed by four cycles of
paclitaxel. Women younger than 50 years with receptor-positive disease and all women older than 50 years received tamoxifen.[84][Level of evidence: 1iiA]

The difference in OS was small (HR, 0.93), however, and not statistically significant (P = .46).

In the Breast Cancer International Research Group's trial (BCIRG-001), the FAC regimen was compared with the docetaxel plus doxorubicin and cyclophosphamide (TAC) regimen in 1,491 women with node-positive disease. Six cycles of either regimen were given as adjuvant postoperative therapy.[85,86][Level of evidence: 1iiA]

There was a 75% DFS rate at 5 years in the TAC group, compared with a 68% DFS rate in the FAC group (P = .001).

Anemia, neutropenia, febrile neutropenia, and infections were more common in the TAC group. No deaths were associated with infections in either group. (Refer to the PDQ summary on Fatigue for information on anemia.)

An Eastern Cooperative Oncology Group–led intergroup trial (E1199 [NCT00004125]) involving 4,950 patients compared, in a factorial design, two schedules (weekly and every 3 weeks) of the two drugs (docetaxel vs. paclitaxel) after standard-dose AC chemotherapy given every 3 weeks.[87][Level of evidence: 1iiA] Study findings include the following:

There was no difference observed in the overall comparison with regard to DFS of docetaxel to paclitaxel (odds ratio [OR], 1.03; 95% CI, 0.91–1.16; P = .61) or between the 1-week and 3-week schedules (OR, 1.06; 95% CI, 0.94–1.20; P = .33).

There was a significant association between the drug administered and schedule for both DFS (0.003) and OS (0.01). Thus, compared with paclitaxel given every 3 weeks, paclitaxel given weekly improved both DFS (OR, 1.27; 95% CI, 1.01–1.57; P = .006) and OS (OR, 1.32; 95% CI, 1.02–1.72; P = .01).

Docetaxel given every 3 weeks was also superior in DFS to paclitaxel given every 3 weeks (OR, 1.23; 95% CI, 1.00–1.52; P = .02), but the difference was not statistically significant for OS (OR, 1.13; 95% CI, 0.88–1.46; P = .25).

Docetaxel given weekly was not superior to paclitaxel given every 3 weeks. There was no stated a priori basis for expecting that varying the schedule of administration would have opposite effects for the two drugs.

Chemotherapy schedule: Dose-density

Historically, adjuvant chemotherapy for breast cancer was given on an every 3-week schedule. Studies sought to determine whether decreasing the duration between chemotherapy cycles could improve clinical outcomes. The overall results of these studies support the use of dose-dense chemotherapy for women with HER2-negative breast cancer.

A U.S. intergroup trial (CLB-9741) of 2,005 node-positive patients compared, in a 2 × 2 factorial design, the use of concurrent AC followed by paclitaxel with sequential doxorubicin, paclitaxel, and cyclophosphamide given every 2 weeks with filgrastim or every 3 weeks.[88][Level of evidence: 1iiA]

At a median follow-up of 68 months, dose-dense treatment improved DFS, the primary end point, in all patient populations (HR, 0.80; P =.018), but not OS (HR, 0.85; P =.12).[89][Level of evidence: 1iiA]

A meta-analysis of dose-dense versus standard dosing included data from ten trials and over 11,000 women.[91]

In three trials that evaluated similar dosing in the treatment arms, dose-dense treatment was associated with an improvement in DFS (HR, 0.83; 95% CI, 0.73–0.94) and OS (HR, 0.84; 95% CI, 0.72–0.98).

In seven trials in which modified doses or regimens were evaluated, improvement in DFS (HR, 0.81; 95% CI, 0.73–0.88) and OS (HR, 0.85; 95% CI, 0.75–0.96) was also seen. The benefit in DFS was seen in women with hormone receptor–negative disease (HR, 0.71; 95% CI, 0.56–0.98), but not in women with hormone receptor–positive disease (HR, 0.92; 95% CI, 0.75–1.12).

Docetaxel and cyclophosphamide

Docetaxel and cyclophosphamide is an acceptable adjuvant chemotherapy regimen.

Evidence (docetaxel and cyclophosphamide):

The regimen of docetaxel and cyclophosphamide (TC) compared with AC (doxorubicin and cyclophosphamide) was studied in 1,016 women with stage I or stage II invasive breast cancer. Patients were randomly assigned to receive four cycles of either TC or AC as adjuvant postoperative therapy.[92,93][Level of evidence: 1iiA]

At 7 years, the DFS and OS demonstrated that four cycles of TC were superior to standard AC for both DFS and OS.[93]

Patients with triple-negative breast cancer (TNBC) tumors and those with HER2-positive tumors treated with trastuzumab who started chemotherapy 61 days or more after surgery had worse survival (TNBC: HR, 1.54; 95% CI, 1.09–2.18; HER2-positive: HR, 3.09; 95% CI, 1.49–6.39) than did those who initiated treatment in the first 30 days after surgery.

Because of the weaknesses and limitations of this study design, the optimal time to initiate adjuvant chemotherapy remains uncertain.

Toxic effects of chemotherapy

Adjuvant chemotherapy is associated with several well-characterized toxic
effects that vary according to the individual drugs used in each regimen.
Common toxic effects include the following:

The use of anthracycline-containing regimens, however—particularly those containing an increased dose of cyclophosphamide—has been associated with a cumulative risk of developing acute leukemia of 0.2% to 1.7% at 5 years.[97,98] This risk increases to more than 4% in patients receiving high cumulative doses of both epirubicin (>720 mg/m2) and cyclophosphamide (>6,300 mg/m2).[99]

Cognitive impairment has been reported to occur after the administration of some chemotherapy regimens.[100] However, data on this topic from prospective, randomized studies are lacking.

The EBCTCG meta-analysis revealed that women who received adjuvant combination
chemotherapy did have a 20% (standard deviation = 10) reduction in the annual
odds of developing contralateral breast cancer.[79] This small proportional
reduction translated into an absolute benefit that was marginally
statistically significant, but indicated that chemotherapy did not increase
the risk of contralateral disease. In addition, the analysis showed no
statistically significant increase in deaths attributed to other cancers or to
vascular causes among all women randomly assigned to receive chemotherapy.

HER2/neu-negative breast cancer

For HER2/neu-negative breast cancer, there is no single adjuvant chemotherapy regimen that is considered standard or superior to another. Preferred regimen options vary by institution, geographic region, and clinician.

Some of the most important data on the benefit of adjuvant chemotherapy came from the EBCTCG, which reviews data from global breast cancer trials every 5 years. In the 2011 EBCTCG meta-analysis, adjuvant chemotherapy using an anthracycline-based regimen compared with no treatment revealed significant improvement in the risk of recurrence (RR, 0.73; 95% CI, 0.68–0.79), significant reduction in breast cancer mortality (RR, 0.79; 95% CI, 0.72–0.85), and significant reduction in overall mortality (RR, 0.84; 95% CI, 0.78–0.91), which translated into an absolute survival gain of 5%.[101]

Triple-negative breast cancer (TNBC)

TNBC is defined as the absence of staining for ER, PR, and HER2/neu. TNBC is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Combination chemotherapy

Evidence (neoadjuvant chemotherapy on a dose-dense or metronomic schedule for TNBC):

A prospective analysis studied 1,118 patients who received neoadjuvant chemotherapy at a single institution, of whom 255 (23%) had TNBC.[103][Level of evidence: 3iiDiv]

The study observed that patients with TNBC had higher pathologic complete response (pCR) rates than did non-TNBC patients (22% vs. 11%; P = .034). Improved pCR rates may be important because in some studies, pCR is associated with improved long-term outcomes.

Platinum agents

Platinum agents have emerged as drugs of interest for the treatment of TNBC. However, there is no established role for adding them to the treatment of early-stage TNBC outside of a clinical trial. One trial that treated 28 women with stage II or stage III TNBC with four cycles of neoadjuvant cisplatin resulted in a 22% pCR rate.[104][Level of evidence: 3iiiDiv] A randomized clinical trial, CALGB-40603 (NCT00861705), evaluated the benefit of carboplatin added to paclitaxel and doxorubicin plus cyclophosphamide chemotherapy in the neoadjuvant setting. The Triple Negative Trial (NCT00532727) is evaluating carboplatin versus docetaxel in the metastatic setting. These trials will help to define the role of platinum agents for the treatment of TNBC.

Poly (ADP-ribose) polymerase (PARP) inhibitor agents

The PARP inhibitors are being evaluated in clinical trials for patients with BRCA mutations and in TNBC.[105] PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. Because TNBC shares multiple clinicopathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms, it is possible that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death.

HER2/neu-positive breast cancer

Treatment options for HER2-positive early breast cancer:

Standard treatment for HER2-positive early breast cancer is 1 year of adjuvant trastuzumab therapy.

Trastuzumab

Several phase III clinical trials have addressed the role of the anti-HER2/neu antibody, trastuzumab, as adjuvant therapy for patients with HER2-overexpressing cancers. Study results confirm the benefit of 12 months of adjuvant trastuzumab therapy.

Evidence (duration of trastuzumab therapy):

The HERA (BIG-01-01 [NCT00045032]) trial examined whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment. For most patients, primary treatment consisted of an anthracycline-containing chemotherapy regimen given preoperatively or postoperatively, plus or minus local-regional radiation therapy. Trastuzumab was given every 3 weeks starting within 7 weeks of the completion of primary treatment.[106][Level of evidence: 1iiA] Patients were randomly assigned to one of three study arms:

Observation (n = 1,693).

1 year of trastuzumab (n = 1,694).

2 years of trastuzumab (n = 1,694).

Of the patients in the comparison of 1 year of trastuzumab versus observation group, the median age was 49 years, about 33% had node-negative disease, and nearly 50% had hormone receptor (ER and PR)–negative disease.[107,108][Level of evidence: 1iiA]

One year of trastuzumab versus observation:

Patients who were treated with 1 year of trastuzumab experienced a 46% lower risk of a first event (HR, 0.54; 95% CI, 0.43–0.67; P < .001), corresponding to an absolute DFS benefit of 8.4% at 2 years (95% CI, 2.1–14.8). The updated results at 23.5 months of follow-up showed an unadjusted HR for the risk of death with trastuzumab compared with observation of 0.66 (95% CI, 0.47–0.91; P = .0115), corresponding to an absolute OS benefit of 2.7%.[107]

There were 218 DFS events reported in the trastuzumab group, compared with 321 DFS events reported in the observation group. The unadjusted HR for the risk of an event with trastuzumab was 0.64 (0.54–0.76; P < .001), corresponding to an absolute DFS benefit of 6.3%.[107]

The benefit of 1 year of trastuzumab over observation persisted, despite crossover of 52% of the patients on observation (HR, 0.76; 95% CI, 0.65–0.88; P = .0005).[108]

One year versus 2 years of trastuzumab:

After a median follow-up of 8 years, the results of the comparison of 1 year versus 2 years of trastuzumab were analyzed.[108] No difference in DFS was found between the groups (HR, 0.99; 95% CI, 0.85–1.14; P = .86).[108]

In the combined analysis of the NSABP-B-31 (NCT00004067) and intergroup NCCTG-N9831 trials, trastuzumab was given weekly, concurrently, or immediately after the paclitaxel component of the AC with paclitaxel regimen.[109,110][Level of evidence: 1iiA]

The HERA results were confirmed in a joint analysis of the two studies, with a combined enrollment of 3,676 patients. A highly statistically significant improvement in DFS (HR, 0.48; P < .001; 3-year DFS, 87% vs. 75%) was observed, as was a significant improvement in OS (HR, 0.67; P = .015; 3-year OS, 94.3% in the trastuzumab group vs. 91.7% in the control group; 4-year OS, 91.4% in the trastuzumab group vs. 86.6% in the control group).[109]

Patients treated with trastuzumab experienced a longer DFS, with a 52% lower risk of a DFS event (HR, 0.48; 95% CI, 0.39–0.59; P < .001), corresponding to an absolute difference in DFS of 11.8% at 3 years and 18% at 4 years. The risk of distant recurrence in patients treated with trastuzumab was 53% lower (HR, 0.47; 95% CI, 0.37–0.61; P < .001), and the risk of death was 33% lower (HR, 0.67; 95% CI, 0.48–0.93; P = .015).[109]

A significant DFS and OS benefit was seen in both groups treated with
trastuzumab compared with the control group that did not receive trastuzumab.

For patients receiving AC-T plus trastuzumab, the 5-year DFS rate was 84% (HR for the comparison with AC-T, 0.64; P < .001), and the OS rate was 92% (HR, 0.63; P < .001). For patients receiving TCH, the 5-year DFS rate was 81% (HR, 0.75; P = .04), and the OS rate was 91% (HR, 0.77; P = .04).
The control group had a 5-year DFS rate of 75% and an OS rate of
87%.

The authors stated that there was no significant difference in DFS or OS between the two trastuzumab-containing regimens.
However, the study was not powered to detect equivalence between the two trastuzumab-containing regimens.

The rates of congestive heart failure (CHF) and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P < .001).

These trial findings raise the question of whether anthracyclines are needed for the adjuvant treatment of HER2-overexpressing breast cancer. The group receiving AC-trastuzumab showed a small but not statistically significant benefit over TCH.

This trial supports the use of TCH as an alternative adjuvant regimen for women with early-stage HER2-overexpressing breast cancer, particularly in those with concerns about cardiac toxic effects.

The Finland Herceptin (FINHER) study assessed the impact of a much shorter course of trastuzumab. In this trial, 232 women younger than 67 years with node-positive or high-risk (>2 cm tumor size) node-negative HER2-overexpressing breast cancer were given nine weekly infusions of trastuzumab concurrently with docetaxel or vinorelbine followed by FEC.[112][Level of evidence: 1iiA]

A number of studies have evaluated the use of subcutaneous (SQ) trastuzumab in the neoadjuvant and adjuvant settings.

Cardiac toxic effects with adjuvant trastuzumab

Cardiac events associated with adjuvant trastuzumab have been reported in multiple studies. Key study results include the following:

In the HERA (BIG-01-01) trial, severe CHF (New York Heart Association class III–IV) occurred in 0.6% of patients treated with trastuzumab.[106] Symptomatic CHF occurred in 1.7% of patients in the trastuzumab arm and 0.06% of patients in the observation arm.

In the NSABP B-31 (NCT00004067) trial, 31 of 850 patients in the trastuzumab arm had confirmed symptomatic cardiac events, compared with 5 of 814 patients in the control arm.[114] The 3-year cumulative incidence of cardiac events for trastuzumab-treated patients was 4.1%, compared with 0.8% of patients in the control arm (95% CI, 1.7%–4.9%).

In the NCCTG-N9831 trial, 39 cardiac events were reported in the three arms over a 3-year period. The 3-year cumulative incidence of cardiac events was 0.35% in arm A (no trastuzumab), 3.5% in arm B (trastuzumab after paclitaxel), and 2.5% in arm C, (trastuzumab concomitant with paclitaxel).

In the AVENTIS-TAX-GMA-302 (BCIRG 006) trial, clinically symptomatic cardiac events were detected in 0.38% of patients in the AC/docetaxel (AC-D) arm, 1.87% of patients in the AC/docetaxel/trastuzumab (AC-DH) arm, and 0.37% of patients in the docetaxel/carboplatin/trastuzumab (DCbH) arm.[115] There was also a statistically significant higher incidence of asymptomatic and persistent decrease in left ventricular ejection fraction (LVEF) in the AC-DH arm than with either the AC-D or DCbH arms.

In the FINHER trial, none of the patients who received trastuzumab experienced clinically significant cardiac events. LVEF was preserved in all of the women receiving trastuzumab, but the number of patients receiving adjuvant trastuzumab was very low.[112]

Lapatinib

Lapatinib is a small-molecule tyrosine kinase inhibitor that is capable of dual-receptor inhibition of both epidermal growth factor receptor and HER2. There are no data supporting the use of lapatinib as part of adjuvant treatment of early-stage HER2/neu-positive breast cancer.

Evidence (against the use of lapatinib for HER2 positive early breast cancer):

In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (ALTTO [NCT00553358]), the role of lapatinib (in combination with, in sequence to, in comparison with, or as an alternative to trastuzumab) in the adjuvant setting was investigated.[116]

Results presented at the 2014 American Society of Clinical Oncology (ASCO) annual meeting revealed that in a comparison of concurrently administered lapatinib and trastuzumab versus trastuzumab alone, the HR for DFS reached 0.84 (97.5% CI, 0.70–1.02) with a p-value of .048, which failed to meet the p ≤ .025 threshold for establishing statistical superiority.

Similarly, sequential use of trastuzumab and lapatinib did not meet the noninferiority criteria compared with trastuzumab alone on the basis of an HR for DFS of 0.96 (97.5% CI, 0.80–1.15); p-value of .610, with a p-value of .025 required for significance.

Hormone receptor–positive therapy

Much of the evidence presented in the following sections on therapy for women with hormone receptor–positive disease has been considered in an ASCO guideline that describes several options for the management of these patients.[117]

Tamoxifen

Tamoxifen has been shown to be of benefit to women with hormone receptor–positive breast cancer.

The EBCTCG performed a meta-analysis of systemic treatment of early breast
cancer by hormone, cytotoxic, or biologic therapy methods in randomized trials
involving 144,939 women with stage I or stage II breast cancer. An analysis published in 2005 included information on 80,273 women in 71 trials of adjuvant tamoxifen.[78][Level of evidence: 1iiA]

In this analysis, the benefit of
tamoxifen was found to be restricted to women with hormone receptor–positive or hormone receptor–unknown
breast tumors. In these women, the 15-year absolute reduction associated with 5 years of use was 12% for
recurrence and 9% for mortality.

Allocation to approximately 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50 years, 50–69 years, ≥70 years), PR status, or other tumor characteristics.

The meta-analysis also confirmed the benefit of adjuvant
tamoxifen in hormone receptor–positive premenopausal women. Women younger than 50 years obtained a degree of benefit from 5 years of tamoxifen similar to that
obtained by older women. In addition, the proportional reductions in both
recurrence and mortality associated with tamoxifen use were similar in women
with either node-negative or node-positive breast cancer, but the absolute
improvement in survival at 10 years was greater in the node-positive breast cancer group (5.3%
vs. 12.5% with 5 years of use).

Similar results were found in the IBCSG-13-93 trial.[118] Of 1,246 women with stage II disease, only the women with hormone receptor–positive disease benefited from tamoxifen.

The optimal duration of tamoxifen use has been addressed by the EBCTCG
meta-analysis and by several large randomized trials.[78,119-122] Ten years of tamoxifen therapy has been shown to be superior to shorter durations of tamoxifen therapy.

Evidence (duration of tamoxifen therapy):

The EBCTCG
meta-analysis demonstrated that 5 years of tamoxifen was superior to shorter durations. The following results were reported:[78]

A highly significant advantage of 5 years versus 1 to 2 years of tamoxifen with respect to the risk of recurrence (proportionate reduction, 15.2%; P <.001) and a less significant advantage with respect to mortality (proportionate reduction, 7.9%; P = .01) was observed.

Long-term follow-up of the Adjuvant Tamoxifen Longer Against Shorter (ATLAS) trial demonstrated that 10 years of tamoxifen therapy was superior to 5 years of tamoxifen therapy. Between 1996 and 2005, 12,894 women with early breast cancer were randomly assigned to 10 years or 5 years of tamoxifen therapy. The following results were reported:[122][Level of Evidence: 1iiA]

Study results revealed that 10 years of tamoxifen reduced the risk of breast cancer recurrence (617 recurrences for 10 years of tamoxifen vs. 711 recurrences for 5 years of tamoxifen; P = .002), reduced breast-cancer mortality (331 deaths for 10 years of tamoxifen vs. 397 deaths for 5 years of tamoxifen; P = .01), and reduced overall mortality (639 deaths for 10 years of tamoxifen vs. 722 deaths for 5 years of tamoxifen; P = .01).

Of note, from the time of the original breast cancer diagnosis, the benefits of 10 years of therapy were less extreme before than after year 10. At 15 years from the time of diagnosis, breast cancer mortality was 15% at 10 years and 12.2% at 5 years.

Compared with 5 years, 10 years of tamoxifen therapy increased the risk of the following:

Pulmonary embolus RR, 1.87 (95% CI, 1.13–3.07; P = .01).

Stroke RR, 1.06 (0.83–1.36).

Ischemic heart disease RR, 0.76 (0.6–0.95; P = .02).

Endometrial cancer RR, 1.74 (1.30–2.34; P = .0002). Notably, the cumulative risk of endometrial cancer during years 5 to 14 from breast cancer diagnosis was 3.1% for women who received 10 years of tamoxifen versus 1.6% for women who received 5 years of tamoxifen. The mortality for years 5 to 14 was 12.2 versus 15 for an absolute mortality reduction of 2.8%.

The results of the ATLAS trial indicated that for women who remained premenopausal after 5 years of adjuvant tamoxifen, continued tamoxifen for 5 more years was beneficial.[122] Women who have become menopausal after 5 years of tamoxifen may also be treated with AI. (Refer to the Aromatase inhibitors section in the Hormone–receptor positive therapy section of this summary for more information.)

Tamoxifen and chemotherapy

Based on the results of an EBCTCG analysis, the use of tamoxifen in women who received adjuvant chemotherapy does not attenuate the benefit of chemotherapy.[78] However, concurrent use of tamoxifen with chemotherapy is less effective than sequential administration.[123]

Ovarian ablation, tamoxifen, and chemotherapy

Evidence suggests ovarian ablation alone is not an effective substitute for other systemic therapies.[124-128] Further, the addition of ovarian ablation to chemotherapy and/or tamoxifen has not been found to significantly improve outcomes.[126,128-131]

Evidence (tamoxifen plus ovarian suppression):

The largest study (SOFT [NCT00066690]) to examine the addition of ovarian ablation to tamoxifen with or without chemotherapy randomly assigned 2,033 premenopausal women (53% of whom had received previous chemotherapy) to tamoxifen or tamoxifen plus ovarian suppression with triptorelin or ablation with surgery or radiation therapy.[132][Level of evidence: 1iiDii]

In a multivariable Cox proportional hazards model, the tamoxifen plus ovarian suppression arm was statistically superior to the tamoxifen alone arm with respect to DFS (HR 0.78; 95% CI, 0.62–0.98; P = .03), but the variables included in this analysis were not stated to be prespecified.

In a subgroup analysis addressing a secondary endpoint (OS), patients who had previously received chemotherapy were found to have a significantly better outcome if they received tamoxifen plus ovarian ablation (interaction P = .03).

The P values in these two secondary analyses were not corrected for multiple comparisons.

Aromatase inhibitors (AI)

In postmenopausal women, the use of AI in sequence with or as a substitute for tamoxifen has been shown to improve DFS, but not OS. These drugs have been studied in several settings.

Initial therapy

Evidence (AI as initial therapy in postmenopausal women):

A large, randomized trial of 9,366 patients compared the use of the AI anastrozole and the combination of anastrozole and tamoxifen with tamoxifen alone as adjuvant therapy for postmenopausal patients with node-negative or node-positive disease. Most (84%) of the patients in the study were hormone–receptor positive. Slightly more than 20% had received chemotherapy.[133]; [134][Level of evidence: 1iDii]

With a median follow-up of 33.3 months, no benefit in DFS was observed for the combination arm relative to tamoxifen alone.[133]

Patients on anastrozole, however, had a significantly longer DFS (HR, 0.83) than those on tamoxifen. In an analysis conducted after a median follow-up of 100 months among hormone receptor–positive patients, DFS was significantly (P = .003) longer in patients on anastrozole (HR, 0.85; 95% CI, 0.76–0.94), but OS was not improved (HR, 0.97; 95% CI, 0.86–1.11; P = .7).[134]

Patients on tamoxifen more frequently developed endometrial cancer and cerebrovascular accidents, whereas patients on anastrozole had more fracture episodes. The frequency of myocardial infarction was similar in both groups. Except for a continued increased frequency of endometrial cancer in the tamoxifen group, these differences did not persist in the posttreatment period.[134]

A large double-blinded randomized trial of 8,010 postmenopausal women with hormone receptor–positive breast cancer compared the use of letrozole with tamoxifen given continuously for 5 years or with crossover to the alternate drug at 2 years.[135] An updated analysis from the Breast International Group (IBCSG-1-98) reported results on the 4,922 women who received tamoxifen or letrozole for 5 years at a median follow-up of 51 months.[136][Level of evidence: 1iDii]

The authors point out that the results of long-term follow-up are confounded because patients on tamoxifen were permitted to take letrozole when the trial was unblinded and, thus, the benefit of letrozole may be underestimated in the intent-to-treat analysis described above.

The mild androgen activity of exemestane prompted a randomized trial to evaluate whether exemestane might be preferable to anastrozole, in terms of its efficacy (event-free survival [EFS]) and toxicity, as upfront therapy for postmenopausal women diagnosed with hormone receptor–positive breast cancer.[138][Level of evidence: 1iiA] The MA27 (NCT00066573) trial randomly assigned 7,576 postmenopausal women to receive 5 years of anastrozole or exemestane.

At a median follow-up of 4.1 years, no difference in efficacy was seen (HR, 1.02; 95% CI, 0.87–1.18, P = .86).[138][Level of evidence: 1iiD]

There was also no significant difference in the impact of the two therapies on bone mineral density or fracture rates.[139][Level of evidence: 1iiD]

AI versus tamoxifen therapy

AI have also been compared with tamoxifen in premenopausal women whose ovarian function was suppressed or ablated. The results of these studies have been conflicting.

Evidence (comparing an AI with tamoxifen in premenopausal women):

In one study, 1,803 women receiving goserelin were randomly assigned to a 2 × 2 factorial design trial comparing anastrozole and tamoxifen, with or without zoledronic acid.[140]

At a median follow-up of 62 months, there was no difference in DFS (HR, 1.08; 95% CI, 0.81–1.44; P = .59).

OS was superior with tamoxifen (HR, 1.75; 95% CI 1.08–2.83; P = .02).

Exemestane has also been compared with tamoxifen in premenopausal women who underwent ovarian ablation in an unblinded study that enrolled 4,690 women.[141][Level of evidence: 1iDii]

The use of exemestane resulted in a significant difference in DFS (HR, 0.72; 95% CI, 0.60–0.85; P < .001; 5-year DFS, 91.1% in the exemestane-ovarian suppression group vs. 87.3% in the tamoxifen-ovarian suppression group).

No difference in OS (HR, 1.14 for death in the exemestane-ovarian suppression group; 95% CI, 0.86–1.51; P = .37; 5-year OS, 95.9% in the exemestane/ovarian suppression group vs. 96.9% in the tamoxifen-ovarian suppression group) was reported.[141][Level of evidence: 1iiA]

Sequential tamoxifen and AI versus 5 years of tamoxifen

Several trials and meta-analyses have examined the effect of switching to anastrozole or exemestane to complete a total of 5 years of therapy after 2 to 3 years of tamoxifen.[142-144] The evidence, as described below, indicates that sequential tamoxifen and AI is superior to remaining on tamoxifen for 5 years.

Evidence (sequential tamoxifen and AI vs. 5 years of tamoxifen):

One study, which included 448 patients, demonstrated a statistically significant reduction in DFS (HR, 0.35; 95% CI, 0.18–0.68; P = .001) but no difference in OS in the anastrozole group.[142][Level of evidence: 1iiA]

Two other trials were reported together.[143] A total of 3,224 patients were randomly assigned after 2 years of tamoxifen to continue tamoxifen for a total of 5 years or to take anastrozole for 3 years. After a median follow-up of 78 months, an improvement in all-cause mortality (HR, 0.61; 95% CI, 0.42–0.88; P = .007) was observed in the anastrozole group.[144]

A large, double-blinded, randomized trial (EORTC-10967 [ICCG-96OEXE031-C1396-BIG9702]) of 4,742 patients compared continuing tamoxifen with switching to exemestane for a total of 5 years of therapy in women who had received 2 to 3 years of tamoxifen.[146][Level of evidence: 1iDii]

After the second planned interim analysis, when median follow-up for patients on the study was 30.6 months, the results were released because of a highly significant (P < .005) difference in DFS (HR, 0.68) favoring the exemestane arm.[146]

After a median follow-up of 55.7 months, the HR for DFS was 0.76 (95% CI, 0.66–0.88; P = .001) in favor of exemestane.[147][Level of evidence: 1iA]

At 2.5 years after random assignment, 3.3% fewer patients on exemestane had developed a DFS event (95% CI, 1.6–4.9). The HR for OS was 0.85 (95% CI, 0.7–1.02; P = .08).[147]

A meta-analysis that included the previous trial along with three other studies found the following:[148][Level of evidence: 1iA]

Sequential tamoxifen and AI for 5 years versus 5 years of an AI

The evidence indicates there is no benefit to the sequential use of tamoxifen and an AI for 5 years over 5 years of an AI.

Evidence (sequential use of tamoxifen and an AI vs. 5 years of an AI):

A large, randomized trial of 9,779 patients compared DFS of postmenopausal women with hormone receptor–positive breast cancer between initial treatment with sequential tamoxifen for 2.5 to 3 years followed by exemestane for a total of 5 years versus exemestane alone for 5 years. The primary endpoints were DFS at 2.75 years and 5.0 years.[149][Level of evidence: 1iDii]

Five-year DFS was 85% in the sequential group and 86% in the exemestane-alone group (HR, 0.97; 95% CI, 0.88–1.08; P = .60).

There was no difference in DFS when the two sequential arms were compared with 5 years of letrozole (letrozole to tamoxifen HR, 1.06; 95% CI, 0.91–1.23; P = .45 and tamoxifen to letrozole HR, 1.07; 95% CI, 0.92–1.25; P = .36).

Switching to an AI after 5 years of tamoxifen

The evidence, as described below, indicates that switching to an AI after 5 years of tamoxifen is superior to stopping tamoxifen at that time.

A large, double-blinded, randomized trial (CAN-NCIC-MA17 [NCT00003140]) of 5,187 patients compared the use of letrozole versus placebo in receptor-positive postmenopausal women who received tamoxifen for approximately 5 (4.5–6.0) years.[151][Level of evidence: 1iDii]

After the first planned interim analysis, when median follow-up for patients on study was 2.4 years, the results were unblinded because of a highly significant (P < .008) difference in DFS (HR, 0.57) favoring the letrozole arm.[151]

After 3 years of follow-up, 4.8% of the women on the letrozole arm had developed recurrent disease or new primaries versus 9.8% on the placebo arm (95% CI for the difference, 2.7%–7.3%). Because of the early unblinding of the study, longer-term comparative data on the risks and benefits of letrozole in this setting will not be available.[152,153]

An updated analysis including all events before unblinding confirmed the results of the interim analysis.[154] In addition, a statistically significant improvement in distant DFS was found for patients on letrozole (HR, 0.60; 95% CI, 0.43–0.84; P = .002). Although no statistically significant difference was found in the total study population, the node-positive patients on letrozole also experienced a statistically significant improvement in OS (HR, 0.61; 95% CI, 0.38–0.98; P = .04), although the P value was not corrected for multiple comparisons.

The NSABP B-33 (NCT00016432) trial that was designed to compare 5 years of exemestane with placebo after 5 years of tamoxifen was stopped prematurely when the results of CAN-NCIC-MA17 became available. At the time of analysis, 560 of the 783 patients who were randomly assigned to exemestane remained on that drug and 344 of the 779 patients who were randomly assigned to receive placebo had crossed over to exemestane.[155][Level of evidence: 1iDii]

Bisphosphonates

The role of bisphosphonates as part of adjuvant therapy for early-stage breast cancer is unclear.

Evidence (bisphosphonates in the treatment of early breast cancer):

The ABCSG-12 (NCT00295646) trial was a 2 × 2 factorial-design randomized trial that assigned 1,803 premenopausal patients with hormone receptor–positive breast cancer to receive ovarian function suppression with goserelin and tamoxifen versus goserelin and anastrozole. These patients then underwent a second random assignment to receive zoledronic acid (4 mg IV every 6 months) or no zoledronic acid.[156][Level of evidence: 1iiA]

The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy alone, resulted in a relative reduction of 36% in the risk of disease progression (HR, 0.64; P = .01) but did not significantly reduce the risk of death.[140]

Results were unchanged in an analysis conducted 2 years after treatment completion.[140]

Similar results were obtained in the NCT00171340 trial in which 1,065 postmenopausal women received letrozole and were randomly assigned to receive zoledronic acid (4 mg IV every 6 months) immediately or only after the development of bone loss or fractures.[157][Level of evidence: 1iiA]

While bisphosphonates appear to improve DFS in a population with low-to-intermediate-risk breast cancer, this benefit does not appear to be seen in all patients with breast cancer. The AZURE trial was a randomized, phase III trial that assigned 3,660 patients with stage II or stage III breast cancer to receive chemotherapy and/or hormone therapy with or without zoledronic acid.[158][Level of evidence: 1iiA]

At a median follow-up of 59 months, there was no significant benefit in DFS in both groups (77% in each group; HR, 0.98; P = .79).

OS was also similar, at 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted HR, 0.85; P = .07).

These three studies, plus several others, have been included in three meta-analyses addressing the question of whether the use of zoledronic acid in the adjuvant setting prolongs survival. The results of these meta-analyses are conflicting. One study found no significant impact on survival (relative risk [RR], .90; 95% CI, 0.61–1.33; P = .61).[160] A second study found a significant effect on survival (HR, .81; 95% CI, .70–.94; P = .007).[161] The third study found a borderline significant effect on survival (RR, .88; 95% CI, 0.77– 1.01; P = .06).[162][Level of evidence: 1iiA]

Based on the conflicting results of these trials, the exact role for bisphosphonates in adjuvant therapy for breast cancer is controversial. An ongoing phase III trial (NCT01077154) is examining the activity of the bone-modifying agent, denosumab, in stage II and stage III breast cancer.

Preoperative Systemic Therapy

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been administered in patients with locally advanced breast cancer in an attempt to reduce tumor volume and allow for definitive surgery. In addition, preoperative chemotherapy is being used for patients with primary operable stage II or stage III breast cancer. A meta-analysis of multiple randomized clinical trials has demonstrated that preoperative chemotherapy is associated with identical DFS and OS compared with the administration of the same therapy in the adjuvant setting.[163][Level of evidence: 1iiA] Current consensus opinion for use of preoperative chemotherapy recommends anthracycline- and taxane-based therapy, and prospective trials suggest that preoperative anthracycline- and taxane-based therapy is associated with higher response rates than alternative regimens (e.g., anthracycline alone).[164,165][Level of evidence: 1iiDiv]

A potential advantage of preoperative systemic therapy is the increased likelihood of success with
definitive local therapy in those presenting with locally-advanced, unresectable disease. It may also offer benefit to carefully selected patients with primary operable disease by enhancing the likelihood of breast conservation, and providing prognostic information where pCR is obtained. In these cases, a patient can be informed that there is a very low risk of recurrence compared with a situation in which a large amount of residual disease remains. Postoperative radiation therapy may also be omitted in a patient with histologically negative axillary nodes after preoperative therapy, irrespective of lymph node status before preoperative therapy, allowing for tailoring of treatment to the individual.

Potential disadvantages with this approach include the inability to determine an accurate pathological stage after preoperative chemotherapy. However, the knowledge of the presence of residual disease may provide more personalized prognostic information, as noted above.

Patient selection, staging, treatment, and follow-up

Multidisciplinary management of patients undergoing preoperative therapy by an experienced team is essential to optimize the following:

Patient selection.

Choice of systemic therapy.

Management of the axilla and surgical approach.

Decision to administer adjuvant radiation therapy.

The tumor histology, grade, and receptor status are carefully evaluated before preoperative therapy is initiated. Patients whose tumors have a pure lobular histology, low grade, or high hormone–receptor expression and HER2-negative status are less likely to respond to chemotherapy and should be considered for primary surgery, especially when the nodes are clinically negative. Even if adjuvant chemotherapy is administered after surgery in these cases, a third-generation regimen (anthracycline/taxane based) may be avoided.

Before beginning preoperative therapy, the extent of the disease within the breast and regional lymph nodes should be assessed. Staging of systemic disease may include the following:[166]

CT scan of the chest and abdomen and a bone scan.

Positron-emission tomography.

Baseline breast imaging is performed when breast-conserving therapy is desired to identify the tumor location and exclude multicentric disease. Suspicious abnormalities are usually biopsied before beginning treatment and a marker placed at the center of the breast tumor(s). When possible, suspicious axillary nodes may be biopsied before initiation of systemic treatment.

The optimal timing of sentinel lymph node (SLN) biopsy has not been established in patients receiving preoperative therapy. The following points should be considered:

If suspicious nodes are positive for malignancy at baseline, an SLN biopsy may be performed after preoperative therapy but is associated with a high false-negative rate. If the procedure is performed with both radiocolloid and blue dye and at least two nodes are sampled (provides 10.8% false-negative rate) and are negative, then axillary lymph node dissection (ALND) may be omitted.[167][Level of evidence: 2Div]; [168][Level of evidence: 3iiD]; [169][Level of evidence: 3iiDiv] Alternatively, it is acceptable in this circumstance to perform ALND based on the possibility of undetected positive nodes.

In patients with clinically negative nodes, SLN biopsy may be performed before preoperative therapy because of the false-negative rates observed when performed after preoperative therapy.[170] If the SLN biopsy is negative, ALND can be omitted.

If SLN biopsy is performed after preoperative chemotherapy, the baseline clinical and postchemotherapy pathological nodal status should be taken into consideration when deciding whether ALND is necessary. ALND is usually performed in the setting of node-positivity.

When considering preoperative therapy, treatment options include the following:

For HER2-negative breast tumors, an anthracycline-taxane based chemotherapy regimen.

For HER2-positive disease, chemotherapy and HER2-targeted therapy.

Ideally, the entire treatment regimen is administered before surgery.

For postmenopausal women with hormone receptor–positive breast cancer, chemotherapy is an option. For those who cannot be given chemotherapy, preoperative endocrine therapy may be an option.

For premenopausal women with hormone–responsive cancer, the use of preoperative endocrine therapy is under investigation.

Regular clinical assessment of response to therapy is necessary after beginning preoperative therapy. Repeat radiographic
assessment is also required if breast conservation is the surgical goal. Patients with progressive disease during preoperative therapy may either transition to a non–cross-resistant regimen or proceed to surgery, if feasible.[171,172] Although switching to a non–cross-resistant regimen results in a higher pCR rate than continuing the same therapy, there is no clear evidence that other breast cancer outcomes are improved with this approach.

HER2/neu-negative breast cancer

Early trials examined whether anthracycline-based regimens used in the adjuvant setting would prolong DFS and OS when used in the preoperative setting. The evidence supports higher rates of breast-conserving therapy with the use of a preoperative anthracycline chemotherapy regimen than with postoperative use, but no improvement in survival was noted with the preoperative strategy.

Evidence (preoperative anthracycline-based regimen):

A randomized clinical trial (NSABP-B-18) was designed to determine whether the preoperative combination of four cycles of AC would more effectively prolong DFS and OS than the same chemotherapy given in the adjuvant setting.[173-175][Level of evidence: 1iiA]

After preoperative therapy, 36% of the patients had a complete clinical response.

More patients
treated with preoperative chemotherapy were able to have breast-conserving
procedures as compared with those patients in the postoperative chemotherapy
group (68% vs. 60%; P = .001).

No statistically significant
difference existed, however, in DFS, distant DFS, or OS in the
patients who received preoperative chemotherapy as compared with those who received
postoperative chemotherapy.

An EORTC randomized trial (EORTC-10902)
likewise demonstrated no improvement in DFS or
OS, but showed an increased frequency of conservative surgery with the
use of preoperative versus postoperative FEC chemotherapy.[176][Level of evidence: 1iiA]

In an effort to improve the results observed with AC alone, a taxane was added to the chemotherapy regimen. The following study results support the addition of a taxane to an anthracycline-based chemotherapy regimen for HER2-negative breast tumors.

The administration of preoperative AC followed by docetaxel was associated with a higher clinical complete response rate compared with the administration of AC alone (63.6% for AC followed by docetaxel and 40.1% for AC alone; P < .001); a higher pCR rate was also observed (26.1% for AC followed by docetaxel and 13.7% for AC alone; P < .001).

Data from NSABP B-27 and the Aberdeen Breast Group Trial support the use of anthracycline- and taxane-based regimens in women with initial response or with relative resistance to anthracyclines.[171]

Alternative anthracycline/taxane schedules have also been evaluated (concurrent TAC) and appear similar in efficacy to the sequential approach described above.[177][Level of evidence: 1iiDiv]

The incorporation of many additional cytotoxic agents to anthracycline- and taxane-based regimens has not offered a significant additional benefit to breast conservation or pCR rate in unselected breast cancer populations.[178][Level of evidence: 1iiDiv]

Promising results have been observed, however, with the addition of carboplatin to anthracycline-taxane combination chemotherapy regimens in patients with triple-negative breast cancer (TNBC). Future definitive studies evaluating survival endpoints and the identification of biomarkers of response or resistance are necessary before the addition of carboplatin to standard preoperative chemotherapy can be considered a new standard of care.

Evidence (adding carboplatin to an anthracycline-taxane based chemotherapy regimen in patients with TNBC):

The pCR rate for the breast and axilla was 54% for the anthracycline/taxane backbone plus carboplatin group versus 41% for the anthracycline/taxane backbone alone group (P = .0029)

Importantly, results of studies in the adjuvant and metastatic settings have not demonstrated an OS benefit with the addition of bevacizumab to chemotherapy versus chemotherapy alone. However, the addition of bevacizumab to preoperative chemotherapy has been associated with an increased pCR rate alongside increased toxicity such as hypertension, cardiac toxicity, hand-foot syndrome, and mucositis (e.g., NSABP B-40 [NCT00408408] and GeparQuinto [NCT00567554]).[181,182][Level of evidence: 1iiDiv] However, it is not clear that the modest benefit observed will translate into a longer term survival advantage.

HER2/neu-positive breast cancer

After the success in the adjuvant setting, initial reports from phase II studies indicated improved pCR rates when trastuzumab, a monoclonal antibody that binds the extracellular domain of HER2, was added to preoperative anthracycline- and taxane-based regimens.[183][Level of evidence: 1iiDiv] This has been confirmed in phase III studies.[184,185]

Trastuzumab

Evidence (trastuzumab):

A phase III study (NOAH) randomly assigned patients with HER2-positive locally advanced or inflammatory breast cancers to preoperative chemotherapy with or without 1 year of trastuzumab therapy.[185][Level of evidence:1iiA]

Study results confirmed that the addition of trastuzumab to preoperative chemotherapy resulted not only in improved clinical responses (87% vs. 74%) and pathologic responses (breast and axilla, 38% vs. 19%) but also in EFS, the primary outcome.[185][Level of evidence:1iiA]

After a median follow-up of 5.4 years, the EFS benefit was 58% with the addition of trastuzumab to chemotherapy (95% CI, 48–66) and 43% (95% CI, 34–52) in patients in the chemotherapy group. The unadjusted HR for EFS between the two randomized HER2-positive treatment groups was 0.64 (95% CI, 0.44–0.93; two-sided log-rank P = .016). EFS was strongly associated with pCR in patients who received trastuzumab.[186]

Symptomatic cardiac failure occurred in two patients who received concurrent doxorubicin and trastuzumab for two cycles. Close cardiac monitoring of LVEF and the total dose of doxorubicin not exceeding 180 mg/m2 accounted for the relatively low number of declines in LVEF and only two cardiac events. (Refer to the Cardiac toxic effects with adjuvant trastuzumab section in this summary for more information.)[185][Level of evidence: 1iiD]

There was no significant difference in pCR rate in the breast between the arms (56.5% sequential, 54.2% concurrent; difference, 2.3% with 95% CI, -9.3–13.9).

In addition, asymptomatic declines in LVEF during preoperative chemotherapy were identified in similar proportions of patients in each arm.

The conclusion was that concurrent administration of trastuzumab with anthracyclines is not warranted based on these findings.

A phase III (HannaH [NCT00950300]) trial also demonstrated that the pharmacokinetics and efficacy of preoperative SQ trastuzumab is noninferior to the IV formulation. This international, open-label trial (n = 596) randomly assigned women with operable, locally advanced, or inflammatory HER2-positive breast cancer to preoperative chemotherapy (anthracycline/taxane-based), concurrent with either SQ-administered or IV-administered trastuzumab every 3 weeks before surgery. Patients received adjuvant trastuzumab to complete 1 year of therapy.[188][Level of evidence: 1iiD] The pCR rates between the arms differed by 4.7% (95% CI, 4.0–13.4); 40.7% in the IV-administered group versus 45.4% in the SQ-administered group, demonstrating noninferiority for the SQ formulation. Data regarding the DFS and OS differences between the arms are not yet available.

An ongoing trial, SafeHer (NCT01566721), is evaluating the safety of self-administered versus clinician-administered SQ trastuzumab. SQ trastuzumab is approved for use in Europe in early- and late-stage breast cancer.

Newer HER2-targeted therapies (lapatinib, pertuzumab) have also been investigated. It appears that dual targeting of the HER2 receptor results in an increase in pCR rate; however, no survival advantage has been demonstrated to date with this approach.[189,190]

Pertuzumab

Pertuzumab is a humanized monoclonal antibody that binds to a distinct epitope on the extracellular domain of the HER2 receptor and inhibits dimerization. Pertuzumab, in combination with trastuzumab with or without chemotherapy, has been evaluated in two preoperative clinical trials in an attempt to improve on the pCR rates observed with trastuzumab and chemotherapy.

Evidence (pertuzumab):

In the open-label, randomized, phase II NeoSPHERE (NCT00545688) trial,[189] 417 women with tumors that were larger than 2 cm or node-positive, and who had HER2-positive breast cancer, were randomly assigned to one of four preoperative regimens:[189][Level of evidence: 1iiDiv]

Docetaxel plus trastuzumab.

Docetaxel plus trastuzumab and pertuzumab.

Pertuzumab plus trastuzumab.

Docetaxel plus pertuzumab.

The following results were observed:

The pCR rates were 29%, 46%, 17%, and 24%, respectively. Therefore, the highest pCR rate was seen in the preoperative treatment arm with dual HER2 blockade plus chemotherapy.

The addition of pertuzumab to the docetaxel plus trastuzumab combination did not appear to increase toxic effects, including the risk of cardiac adverse events.

The open-label, randomized, phase II TRYPHAENA (NCT00976989) trial sought to evaluate the tolerability and activity associated with trastuzumab and pertuzumab.[191][Level of evidence: 1iiDiv] All 225 women with tumors that were larger than 2 cm or node-positive, and who had operable, locally advanced, or inflammatory HER2-positive breast cancer, were randomly assigned to one of three preoperative regimens:

The pCR rate was equivalent across all three treatment arms (62%, 57%, and 66%, respectively).

All three arms were associated with a low incidence of cardiac adverse events of 5% or less.

On the basis of these studies, the FDA-granted accelerated approval for the use of pertuzumab as part of preoperative treatment for women with early-stage, HER2-positive breast cancer whose tumors are larger than 2 cm or node-positive. The FDA approved no more than three to six cycles of pertuzumab. Thus, a pertuzumab-based regimen as outlined above is a new treatment option for patients with HER2-positive breast cancer who are candidates for preoperative therapy. There is insufficient evidence to recommend concomitant anthracycline/pertuzumab or sequential use of doxorubicin with pertuzumab.

The ongoing APHINITY (NCT01358877) trial, a randomized, phase III, adjuvant study for women with HER2-positive breast cancer, is the confirmatory trial for this accelerated approval. Results are expected in 2016.

Cardiac toxic effects with pertuzumab

A pooled analysis of cardiac safety in 598 cancer patients treated with pertuzumab was performed using data supplied by Roche and Genentech.[192][Level of evidence: 3iiiD]

Lapatinib

Lapatinib is a small-molecule kinase inhibitor that is capable of dual receptor inhibition of both epidermal growth factor receptor and HER2. Study results do not support the use of lapatinib in the preoperative setting.

Evidence (lapatinib):

The role of lapatinib in the preoperative setting was examined in the GeparQuinto [NCT00567554] trial.[182] This phase III trial randomly assigned women with HER2-positive early-stage breast cancer to receive chemotherapy with trastuzumab or chemotherapy with lapatinib, with pCR as the primary endpoint.[182][Level of evidence: 1iiDiv]

pCR in the chemotherapy and lapatinib arm was significantly lower than it was with chemotherapy and trastuzumab (22.7% vs. 30.3%; P = .04).

Other endpoints of DFS, RFS, and OS have not been reported.

Preoperative therapy with dual HER2 inhibition was studied in the NeoALTTO [NCT00553358] trial.[190][Level of evidence: 1iiDiv] This phase III trial randomly assigned 455 women with HER2-positive early-stage breast cancer (tumor size >2 cm) to receive preoperative lapatinib, preoperative trastuzumab, or preoperative lapatinib plus trastuzumab. This anti-HER2 therapy was given alone for 6 weeks and then weekly paclitaxel was added to the regimen for an additional 12 weeks for all enrolled patients. The primary endpoint of this study was pCR.

No significant difference in pCR was seen between the lapatinib (24.7%, 95% CI, 18.1–32.3) and trastuzumab groups (difference, -4.8%, -17.6–8.2; P = .34).

More definitive efficacy data were provided by the phase III ALLTO (NCT00490139) trial that randomly assigned women to trastuzumab or trastuzumab plus lapatinib in the adjuvant setting.[116] The trial did not meet its primary endpoint of DFS. The doubling in pCR rate observed with the addition of lapatinib to trastuzumab in the NeoALTTO trial did not translate into improved survival outcomes in the ALTTO trial at 4.5 years of median follow-up. This indicates that there is currently no role for the use of lapatinib in the preoperative or adjuvant settings.

Preoperative endocrine therapy

Preoperative endocrine therapy may be an option for postmenopausal women with hormone receptor–positive breast cancer when chemotherapy is not a suitable option because of comorbidities or performance status. Although the toxicity profile of preoperative hormonal therapy over the course of 3 to 6 months is favorable, the pCR rates obtained (1%–8%) are far lower than have been reported with chemotherapy in unselected populations.[193][Level of Evidence: 1iDiv]

Longer duration of preoperative therapy may be required in this patient population. Preoperative tamoxifen was associated with an overall response rate of 33%, with maximum response occurring up to 12 months after therapy in some patients.[194] A randomized study of 4, 8, or 12 months of preoperative letrozole in elderly patients who were not fit for chemotherapy indicated that the longer duration of therapy resulted in the highest pCR rate (17.5% vs. 5% vs. 2.5%, P-value for trend < .04).[165][Level of Evidence: 1iiDiv]

The AI have also been compared with tamoxifen in the preoperative setting. Overall objective response and breast-conserving therapy rates with 3 to 4 months preoperative therapy were either statistically significantly improved in the AI-treated women [193] or comparable to tamoxifen-associated outcomes.[165] An American College of Surgeons Oncology Group trial is currently comparing the efficacy of anastrozole, letrozole, or exemestane in the preoperative setting.

The use of preoperative endocrine therapy in premenopausal women with hormone-responsive breast cancer remains investigational.

Postoperative therapy

There is currently no clear role for adjuvant chemotherapy in cases in which pCR is not obtained after receipt of an anthracycline/taxane combination chemotherapy regimen. Clinical trials of novel therapies should be considered in these individuals (after neoadjuvant or preoperative trials).

Radiation therapy is administered after breast conservation in most women who have received preoperative therapy to reduce the risk of local-regional recurrence. Baseline clinical and subsequent pathologic staging should be considered in deciding whether to administer postmastectomy radiation.

Other adjuvant systemic treatments may be administered either postoperatively or during/after completion of adjuvant radiation, including adjuvant hormonal therapy for patients with hormone receptor–positive disease and adjuvant trastuzumab for those with HER2-positive disease.

Posttherapy Surveillance

The frequency of follow-up and the
appropriateness of screening tests after the completion of primary treatment
for stage I, stage II, or stage III breast cancer remain controversial.

Evidence from randomized trials indicates that periodic follow-up with bone
scans, liver sonography, chest x-rays, and blood tests of liver function does not
improve survival or quality of life when compared with routine physical
examinations.[195-197]
Even when these tests permit earlier detection of
recurrent disease, patient survival is unaffected.[196] On the basis of these data,
acceptable follow-up can be limited to the following for asymptomatic patients who complete treatment for stages I to III breast cancer:

Clarke M, Collins R, Darby S, et al.: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 366 (9503): 2087-106, 2005. [PUBMED Abstract]

Inoperable Stage IIIB or IIIC or Inflammatory Breast Cancer

Multimodality therapy delivered with curative intent is the standard of care
for patients with clinical stage IIIB disease. In a retrospective series, approximately 32% of patients with ipsilateral supraclavicular node involvement and no evidence of distant metastases (pN3c) had prolonged disease-free survival (DFS) at 10 years with combined modality therapy.[1] Although these results have not been replicated in another series, this result suggests such patients should be treated with the same intent.

Initial surgery is generally
limited to biopsy to permit the determination of histology, estrogen-receptor (ER) and progesterone-receptor (PR) levels,
and human epidermal growth factor receptor 2 (HER2/neu) overexpression. Initial treatment with anthracycline-based
chemotherapy and/or taxane-based therapy is standard.[2,3] In one series of
178 patients with inflammatory breast cancer, DFS was 28% at
15 years with a combined-modality approach.[2][Level of evidence: 3iiiDii] For
patients who respond to neoadjuvant chemotherapy, local therapy may consist of
total mastectomy with axillary lymph node dissection followed by postoperative
radiation therapy to the chest wall and regional lymphatics. Breast-conserving
therapy can be considered in patients with a good partial or complete response
to neoadjuvant chemotherapy.[3] Subsequent systemic therapy may consist of
further chemotherapy. Hormone therapy should be administered to patients whose
tumors are ER-positive or unknown. All patients should be considered
candidates for clinical trials to evaluate the most appropriate fashion in
which to administer the various components of multimodality regimens.

Stage IV, Recurrent, and Metastatic Breast Cancer

Recurrent breast cancer is often responsive to therapy, though treatment is
rarely curative at this stage of disease. Patients with localized
breast or chest wall recurrences, however, may be long-term survivors with appropriate
therapy. Prior to treatment for recurrent or metastatic cancer,
restaging to evaluate extent of disease is indicated. Cytologic or histologic
documentation of recurrent or metastatic disease should be obtained whenever
possible. The ER levels and PR levels,
HER2/neu positivity at the time of recurrence, and previous treatment should be
considered, if known, when selecting therapy. ER status may change at the time
of recurrence. In a single small study by the Cancer and Leukemia Group B (MDA-MBDT-8081), 36% of hormone receptor–positive
tumors were found to be receptor negative in biopsy specimens isolated at the
time of recurrence.[4] Patients in this study had no interval treatment. If
ER and PR status is unknown, then the site(s) of recurrence, disease-free
interval, response to previous treatment, and menopausal status are useful in
selecting chemotherapy or hormone therapy.[5]

Recurrent local-regional breast cancer

Patients with local-regional breast cancer recurrence may become long-term survivors
with appropriate therapy. A clinical trial indicated that between 10% and 20%
of patients will have locally recurrent disease in the breast between 1 and 9
years after breast-conserving surgery plus radiation therapy.[6] Nine
percent to 25% of these patients will have distant metastases or locally
extensive disease at the time of recurrence.[7-9] Patients with local-regional
recurrence should be considered for further local treatment (e.g., mastectomy).
In one series, the 5-year actuarial rate of relapse for patients treated for
invasive recurrence after initial breast conservation and radiation therapy was
52%.[8] A phase III, randomized study showed that local control of cutaneous metastases could be achieved with the application of topical miltefosine; however, the drug is not currently available in the United States.[10][Level of evidence: 1iiDiii]

Local chest wall recurrence following mastectomy is usually the harbinger of
widespread disease, but, in a subset of patients, it may be the only site of
recurrence. For patients in this subset, surgery and/or radiation therapy may
be curative.[11,12] Patients with chest wall recurrences of less than 3
cm, axillary and internal mammary node recurrence (not
supraclavicular, which has a poorer survival), and a greater than 2-year
disease-free interval prior to recurrence have the best chance for prolonged
survival.[12] The 5-year disease-free survival DFS rate in one series of such
patients was 25%, with a 10-year rate of 15%.[13] The local-regional control
rate was 57% at 10 years. Systemic therapy should be considered in patients
with local regional recurrence because of the high risk of subsequent metastases.[14] No randomized controlled studies are available to guide patient care in this
situation.

Stage IV and metastatic disease

Systemic disease

Treatment for systemic disease is palliative in intent. Goals of treatment
include improving quality of life and prolongation of life. Although median
survival has been reported to be 18 to 24 months,[15] some patients experience
long-term survival. Among patients treated with systemic chemotherapy at a
single institution between 1973 and 1982, 263 patients (16.6%) achieved
complete responses. Of those, 49 patients (3.1% of the total group) remained
in complete remission for more than 5 years, and 26 patients (1.5%) were still
in complete remission at 16 years.[16][Level of evidence: 3iiDiii]

Treatment of metastatic breast cancer will usually involve hormone therapy
and/or chemotherapy with or without trastuzumab. Radiation therapy
and/or surgery may be indicated for patients with limited symptomatic
metastases. All patients with metastatic or recurrent breast cancer should be
considered candidates for ongoing clinical trials.

Surgery

Surgery may be indicated for selected patients. Examples include patients who
need mastectomies for fungating/painful breast lesions, parenchymal brain or
vertebral metastases with spinal cord compression, isolated lung metastases,
pathologic (or impending) fractures, or pleural or pericardial effusions.
(Refer to the PDQ summary on Pain for more information and for information on pleural and pericardial effusions, refer to the PDQ summary on Cardiopulmonary Syndromes.)

Radiation therapy

Radiation therapy has a major role in the palliation of localized symptomatic
metastases. Indications include painful bony metastases, unresectable central
nervous system metastases (i.e., brain, meningeal, and spinal cord), bronchial
obstruction, and fungating/painful breast or chest wall lesions. Radiation
therapy should also be given following surgery for decompression of
intracranial or spinal cord metastases and following fixation of pathologic
fractures. Clinical trials (including the completed Radiation Therapy Oncology Group's (RTOG) trial [RTOG-9714]) are exploring the optimal radiation fractionation
schedule. Strontium 89, a systemically administered radionuclide, can be
administered for palliation of diffuse bony metastases.[17,18]
(Refer to the PDQ summary on Pain for more information.)

Systemic Therapy

Bisphosphonates

The use of bisphosphonates to reduce skeletal morbidity in patients with bone
metastases should be considered.[19] Results of randomized trials of
pamidronate and clodronate in patients with bony metastatic disease show
decreased skeletal morbidity.[20-22][Level of evidence: 1iC] Zoledronate has been at least as effective as pamidronate.[23] (Refer to the PDQ summary on Pain for more information on bisphosphonates.)

Hormone therapy

Hormone therapy should generally be considered as initial treatment for a
postmenopausal patient with newly diagnosed metastatic disease if the patient’s
tumor is ER-positive, PR-positive, or ER/PR-unknown. Hormone therapy is
especially indicated if the patient’s disease involves only bone and soft
tissue and the patient has either not received adjuvant antiestrogen therapy or
has been off such therapy for more than 1 year. While tamoxifen has been used
in this setting for many years, several randomized trials suggest equivalent or superior response rates and progression-free survival (PFS) for the aromatase inhibitors (AIs) compared with tamoxifen.[24-26][Level of evidence: 1iiDiii] In a meta-analysis that included randomized trials in patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (anastrozole, letrozole, exemestane, or vorozole) lived longer (hazard ratio [HR] for death, 0.87; 95% confidence interval [CI], 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA]

Several randomized but underpowered trials have tried to determine if combined
hormone therapy (luteinizing hormone-releasing hormone [LHRH] agonists + tamoxifen) is superior to either approach
alone in premenopausal women. Results have been inconsistent.[28-30] The best
study design compared buserelin (an LHRH agonist) versus tamoxifen versus the
combination in 161 premenopausal women with hormone receptor–positive
tumors.[31] Patients receiving buserelin and tamoxifen had a significantly
improved median survival of 3.7 years compared with those receiving tamoxifen or
buserelin who survived 2.9 and 2.5 years, respectively (P = .01).[31][Level of evidence: 1iiA] Very few women in this trial received adjuvant tamoxifen,
which makes it difficult to assess whether these results are applicable to women
who relapse after adjuvant tamoxifen.

Women whose tumors are ER-positive or unknown, with bone or soft tissue
metastases only, who have received an antiestrogen within the past year, should
be given second-line hormone therapy. Examples of second-line hormone therapy
in postmenopausal women include selective AIs, such as
anastrozole, letrozole, or exemestane; megestrol acetate; estrogens;
androgens;[32-40] and the ER down-regulator, fulvestrant.[41,42] In comparison to megestrol
acetate, all three currently available AIs have demonstrated, in
prospective randomized trials, at least equal efficacy and better
tolerability.[32-38,43] In a meta-analysis that included randomized trials of patients who were receiving an AI as either their first or second hormonal therapy for metastatic disease, those who were randomly assigned to a third-generation drug (e.g., anastrozole, letrozole, exemestane, or vorozole) lived longer (HRdeath 0.87; 95% CI, 0.82–0.93) than those who received standard therapy (tamoxifen or a progestational agent).[27][Level of evidence: 1iA] Two randomized trials that enrolled 400 and 451
patients who had progressed after receiving tamoxifen demonstrated that
fulvestrant yielded similar results to anastrozole in terms of its impact on PFS.[44,45] The proper sequence of these therapies is currently not known.[43,46]
While there is a biologic rationale for combining fulvestrant with a third-generation AI for patients with recurrent or metastatic disease, the benefits of such combination therapy have not been established.[47]

Premenopausal women should undergo oophorectomy (surgically, with external-beam
radiation therapy or with an LHRH agonist).[48] Patients with lymphangitic
pulmonary metastases, major liver involvement, and/or central nervous system
involvement should not receive hormone therapy as a single modality. Patients
with structural compromise of weight-bearing bones should be considered for
surgical intervention and/or radiation in addition to systemic therapy.
Patients with vertebral body involvement should be evaluated for impending cord
compression even in the absence of neurologic symptoms. Increasing bone pain
and increasing alkaline phosphatase within the first several weeks of hormone
therapy does not necessarily imply disease progression.[49] Patients with
extensive bony disease are at risk for the development of symptomatic
hypercalcemia early in the course of hormone therapy.[49] Early failure (e.g.,
<6 months) on hormone therapy suggests that cytotoxic chemotherapy should be
the next modality employed.

The Breast Cancer Trial of Oral Everolimus (BOLERO-2 [NCT00863655]) , is a randomized, phase III, placebo-controlled trial, of randomly assigned patients with HR+ metastatic breast cancer resistant to nonsteroidal aromatase inhibition who received the mTOR inhibitor everolimus plus exemestane versus placebo plus exemestane.[50][Level of Evidence: 1iDiii] At the interim analysis, median PFS was 6.9 months for everolimus plus exemestane and 2.8 months for placebo plus exemestane (HR, 0.43; 95% CI, 0.35–0.54; P < .001). The addition of everolimus to exemestane was more toxic with the most common grade 3 or 4 adverse events (AEs) being stomatitis (8% vs. 1%), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). The results of this study report a benefit in PFS with the addition of an mTOR inhibitor to endocrine therapy but there were more side effects. Final overall survival (OS) outcomes on this trial are awaited.

Evidence of mTOR inhibitor activity in HER2-positive breast cancer was shown in the phase III BOLERO-3 (NCT01007942) trial.[51][Level of evidence: 1iDiii] In the BOLERO-3 trial, 569 patients with HER2-positive, trastuzumab-resistant breast cancer, who had received previous taxane therapy, were randomly assigned to receive either everolimus plus trastuzumab plus vinorelbine or placebo plus trastuzumab plus vinorelbine. At median follow-up of 20.2 months, median PFS was 7.0 months in the everolimus group versus 5.78 months in the placebo group (HR, 0.78; 95% CI, 0.65–0.95; P = .0067). Serious AEs were reported in 117 patients (42%) in the everolimus group and 55 patients (20%) in the placebo group. Final OS outcomes for this trial have not yet been reported.

Palbociclib

Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) have been implicated in the continued proliferation of hormone receptor–positive breast cancer resistant to endocrine therapy. Palbociclib is an orally available CDK4/6 inhibitor that has been shown in two trials to enhance the efficacy of endocrine therapy.

PALOMA-1/TRIO-18 (NCT00721409) is an open-label, randomized, phase II trial that compared letrozole alone to palbociclib plus letrozole as the initial therapy for estrogen receptor–positive postmenopausal patients with advanced disease. Patients were enrolled in two cohorts, the first selected on the basis of ER positivity, the second on the basis of a potentially predictive molecular abnormality (CCND1 amplification or p16 loss). Results from the two cohorts were combined when no difference in efficacy of palbociclib plus letrozole in the biomarker subgroups was found. Over 2.5 years, 165 patients were enrolled in the trial. At the time of the final analysis of investigator-assessed PFS, the median PFS in the letrozole-alone group was 10.2 months, versus 20.2 months in the letrozole-plus-palbociclib group (HR 0.488; 95% CI, 0.319–0.748; one-sided P = .0004).[52][Level of evidence: 1iiDiii] Mature OS data are not available. Patients receiving palbociclib experienced more frequent cytopenias, fatigue, and nausea, but grade 3 adverse events aside from cytopenias were uncommon, and there were no episodes of febrile neutropenia. However, more patients on the palbociclib-letrozole arm discontinued treatment for adverse events (13%) than did those on the letrozole-alone arm (2%). The U.S. Food and Drug Administration granted accelerated approval to palbociclib on the basis of these results.

PALOMA3 (NCT01942135) is a double-blind, phase III trial that randomly assigned 521 patients with HR-positive, HER2/neu–negative, advanced breast cancer who had relapsed from or progressed on prior endocrine therapy to receive fulvestrant or fulvestrant plus palbociclib. Pre- and postmenopausal patients were eligible. Premenopausal patients received goserelin. The preplanned stopping boundary was crossed at the time of the first interim analysis of investigator-assessed PFS. This analysis showed a median PFS of 9.2 months on the palbociclib-fulvestrant arm versus 3.8 months on the placebo-fulvestrant arm (HR 0.42; 95% CI, 0.32–0.56; P < .001).[53][Level of Evidence: 1iC] Cytopenias, particularly neutropenia, were much more frequent on the palbociclib-containing arm, but febrile neutropenia was very uncommon (0.6%) on both arms. Patients receiving palbociclib had more frequent fatigue, nausea, and headache. Global quality of life as assessed by the European Organisation for Research and Treatment of Cancer questionnaire QLQ-C30 was better maintained on the palbociclib-fulvestrant arm (mean change, -0.9 points vs. -4.0 points; P = 0.03). Patients are continuing on blinded therapy; OS results are not yet available.

Trastuzumab

Approximately 25% of patients with breast cancer have tumors that overexpress
HER2/neu.[54] Trastuzumab is a humanized monoclonal antibody that
binds to the HER2/neu receptor.[54] In patients previously treated with
cytotoxic chemotherapy whose tumors overexpress HER2/neu, administration of
trastuzumab as a single agent resulted in a response rate of 21%.[55][Level of evidence: 3iiiDiv] In a prospective trial, patients with metastatic disease
were randomly assigned to receive either chemotherapy alone (doxorubicin and
cyclophosphamide or paclitaxel) or the same chemotherapy and trastuzumab.
Patients treated with chemotherapy plus trastuzumab had an OS advantage as compared with those receiving chemotherapy alone (25.1 months vs.
20.3 months, P = .05).[56][Level of evidence: 1iiA] When combined with
doxorubicin, trastuzumab is associated with significant cardiac toxicity.[57]
Consequently, patients with metastatic breast cancer with substantial
overexpression of HER2/neu are candidates for treatment with the combination of
trastuzumab and paclitaxel or for clinical studies of trastuzumab combined with
taxanes and other chemotherapeutic agents.[58]

Pertuzumab

Pertuzumab is a humanized, monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than trastuzumab. The binding of pertuzumab to HER2 prevents dimerization with other ligand-activated HER receptors, most notably HER3. Given their potentially complementary mechanisms of action, the phase III CLEOPATRA [NCT00567190] trial assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first-line HER2+ metastatic setting.[61,62][Level of evidence: 1iA] With a median follow-up of 50 months, the median OS was 40.8 months in the control group and 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI, 0.56–0.84; P < .001). Median PFS per investigator assessment was improved by 6.3 months with the addition of pertuzumab (HR, 0.68; 95% CI, 0.58–0.80). The toxicity profile was similar in both treatment groups with no increase in cardiac toxic effects seen in the pertuzumab combination arm.

Ado-trastuzumab emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that incorporates the HER2–targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue. The phase III EMILIA or TDM4370g (NCT00829166)
study was a randomized, open-label trial enrolling 991 patients with HER2-overexpressing, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane.[63][Level of evidence: 1iiA]

Evidence of activity of T-DM1 in heavily pretreated patients with metastatic, HER2-overexpressed breast cancer who had received previous trastuzumab and lapatinib was shown in the randomized, phase III, TH3RESA (NCT01419197) study of T-DM1 versus physician’s choice of treatment.[65][Level of evidence: 1iiA] This trial randomly assigned 602 patients in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and allowed crossover to T-DM1. At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s choice group (HR, 0.528; 95% CI, 0.422–0.661); P < .0001). Interim OS analysis showed a trend favoring T-DM1, but the stopping boundary was not crossed (HR, 0.552; 95% CI, 0.369–0.826; P = .003).

Lapatinib

Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor.

Lapatinib plus capecitabine

Lapatinib has shown activity in combination with capecitabine in patients who have HER2-positive metastatic breast cancer that progressed after treatment with trastuzumab. A nonblinded, randomized trial (GSK-EGF100151) compared the combination of capecitabine and lapatinib with capecitabine alone in 324 patients with locally advanced or metastatic disease that progressed after therapies that included anthracyclines, taxanes, and trastuzumab.[66] At the first planned interim analysis of the trial, a highly significant difference was found that favored the combination arm with respect to the primary study endpoint and time to progression (median time to progression 8.4 months vs. 4.4 months; HR, 0.49; 95% CI, 0.34–0.71; P < .001). There was no difference in OS (HR, 0.92; 95% CI, 0.58–1.46; P = .72).[66][Level of evidence: 1iiA] Patients on combination therapy were more likely to develop diarrhea, rash, and dyspepsia. No data on quality of life or treatment after progression are available. (Refer to the PDQ summary on Gastrointestinal Complications for more information on diarrhea.)

Lapatinib plus trastuzumab

The combination of lapatinib and trastuzumab has been evaluated for patients with HER2-positive metastatic breast cancer whose disease progressed while they were being treated with trastuzumab in a phase III trial.[67][Level of evidence: 1iiA] A total of 291 patients were randomly assigned to treatment with lapatinib alone or in combination with trastuzumab. Compared with lapatinib alone, the combination of lapatinib and trastuzumab significantly improved PFS (HR, 0.74; 95% CI, 0.58–0.94; median, 11 weeks vs. 8 weeks) and OS (HR, 0.74; 95% CI, 0.57–0.97; median, 14 months vs. 10 months). The control arm of lapatinib alone is a nonstandard treatment arm. These data offer heavily pretreated metastatic HER2-positive breast cancer patients an alternative chemotherapy-free treatment regimen using dual HER2 blockade.

Lapatinib plus paclitaxel

A double-blind, randomized phase III study compared paclitaxel and lapatinib with paclitaxel plus placebo as first-line therapy in patients with metastatic breast cancer.[68] In the intention-to-treat population, no benefit was found with the combination treatment. However, specimens were evaluated retrospectively to determine HER2/neu status. When used in HER2/neu-positive patients, treatment with paclitaxel and lapatinib showed improvement in time to progression, event-free survival, response rate, and clinical benefit rate; OS did not increase. Toxicities, specifically alopecia, diarrhea, and rash were higher in the HER2/neu-positive lapatinib group. A series of AE were low and existed in both arms.[68][Level of evidence: 1iDiii]

Cytotoxic chemotherapy

Patients whose tumors have progressed on hormone therapy are candidates for
cytotoxic chemotherapy. Patients with hormone receptor–negative tumors and
those with visceral metastases are also candidates for cytotoxic agents.[69]

Single agents that have shown activity in metastatic breast cancer include the following:

Whether single-agent chemotherapy or combination chemotherapy
is preferable for first-line treatment is unclear. An Eastern Cooperative Oncology Intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin given both as a combination and sequentially.[94] Although response rate and time-to-progression were both better for the combination, survival was the same in both groups.[94][Level of evidence: 1iiA];[95,96] The rate of disease progression,
the presence or absence of comorbid medical conditions, and physician/patient
preference will influence the choice of therapy in individual patients. At
this time, no data support the superiority of any particular
regimen. Sequential use of single agents or combinations can be used for
patients who relapse. Combinations of chemotherapy and hormone therapy have
not shown an OS advantage over the sequential use of these
agents.[15,97]
A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response but had no effect on OS.[98][Level of evidence: 1iiA]

The optimal treatment duration for patients with responsive or stable disease
has been studied by several groups. For patients who attain a complete
response to initial therapy, two randomized trials have shown a prolonged
DFS from immediate treatment with a different chemotherapy
regimen compared to observation with treatment upon relapse.[99,100][Level of evidence: 1iiA] Neither of these
studies, however, showed an improvement in OS for patients who received
immediate treatment, and in one of these studies,[100] survival was actually
worse in the immediately treated group. Similarly, no difference in survival
was noted when patients with partial response or stable disease after initial
therapy were randomized to receive either a different chemotherapy versus
observation [101] or a different chemotherapy regimen given at higher versus
lower doses.[102][Level of evidence: 1iiA] These four studies indicate that
different combination regimens of additional chemotherapy immediately following
a patient’s best response to an induction chemotherapy regimen does not improve
OS. In view of the lack of a standard approach, patients
requiring second-line regimens are good candidates for clinical trials.

The potential for doxorubicin-induced cardiac toxic effects should be considered in
the selection of chemotherapeutic regimens for an individual patient.
Recognized risk factors for cardiac toxicity include advanced age, prior
chest-wall radiation therapy, prior anthracycline exposure, hypertension, diabetes,
and known underlying heart disease. The cardioprotective drug, dexrazoxane, has
been shown to decrease the risk of doxorubicin-induced cardiac toxicity in
patients in controlled studies. The use of this agent has permitted patients
to receive greater cumulative doses of doxorubicin and allowed patients with
cardiac risk factors to receive doxorubicin.[103-106] Dexrazoxane has a similar
protective effect in patients receiving epirubicin.[107] The risks of cardiac
toxicity may also be reduced by administering doxorubicin as a continuous
intravenous infusion.[108]

Studies comparing high-dose chemotherapy with stem cell support to conventional
chemotherapy in patients with metastatic disease indicate no
OS or relapse-free survival benefit for patients receiving high-dose
chemotherapy with stem cell support.[109,110][Level of evidence: 1iiA] In the
absence of data suggesting a benefit from high-dose chemotherapy with stem cell
support, this remains an area of clinical evaluation.[111,112]

Bevacizumab

Bevacizumab is a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A. Its role in the treatment of metastatic breast cancer remains controversial. The efficacy and safety of bevacizumab as a second- and third-line treatment for patients with metastatic breast cancer were studied in a single, open-label, randomized trial.[113] The study enrolled 462 patients who had received prior anthracycline and taxane therapy and were randomly assigned to receive capecitabine with or without bevacizumab. The study failed to demonstrate a statistically significant effect on PFS (4.86 months vs. 4.17 months; HR, 0.98) or OS (15.1 months vs. 14.5 months).[113][Level of Evidence: 1iiA]

The AVADO (NCT00333775) trial randomly assigned 736 patients to docetaxel plus either placebo or bevacizumab at 7.5 mg/kg or 15 mg/kg every 3 weeks as the initial treatment for patients with metastatic breast cancer. The combination of bevacizumab at 15 mg/kg, but not 7.5 mg/kg, with docetaxel modestly improved median PFS compared with placebo (10.1 months vs. 8.1 months) but did not improve OS (30.2 months vs. 31.9 months; P = .85).[115][Level of Evidence: 1iiA] Again, more toxic effects were seen in patients in the bevacizumab-containing arms with significantly higher rates of bleeding and hypertension compared with the placebo arms.

The RIBBON-2 (NCT00281697) trial studied the efficacy of bevacizumab as a second-line treatment for metastatic breast cancer.[117] This trial randomly assigned 684 patients in a 2:1 fashion to standard chemotherapy plus bevacizumab or standard chemotherapy plus placebo. Median PFS increased from 5.1 to 7.2 months for the bevacizumab-containing treatment arm (stratified HR for PFS, 0.78; 95% CI, 0.64 to 0.93; P = .0072). However, no statistically significant difference in OS was seen (16.4 months vs. 18.0 months for chemotherapy plus placebo vs. chemotherapy plus bevacizumab, respectively, P = .3741).[117][Level of evidence: 1iA] Toxicities associated with bevacizumab were again similar to those seen in prior clinical trials.

In November 2011, based on the consistent finding that bevacizumab only modestly improved PFS but not OS, and given bevacizumab’s considerable toxicity profile, the Food and Drug Administration revoked approval of bevacizumab for the treatment of metastatic breast cancer.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of breast cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.

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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

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The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

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Updated: July
24, 2015

This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.